STUDIES  ON  THE  QUANTITATIVE 
ESTIMATION  OF  ALKALOIDS  BY 
MEANS  OF  IMMISCIBLE  SOLVENTS 


BY 

HARRY  FLETCHER  LEWIS 

B.S.  WESLEYAN  UNIVERSITY,  1912;  M.S.  WESLEYAN  UNIVERSITY,  I913 


wffiOTY  r  'y"*  ir- 


j  V  ,1. 


THESIS 


Submitted  in  Partial  Fulfillment  of  the  Requirements  for  the  Degree  of 


DOCTOR  OF  PHILOSOPHY 
IN  CHEMISTRY 


IN 

THE  GRADUATE  SCHOOL  OF  THE 
UNIVERSITY  OF  ILLINOIS 

1916 


TABLE  OF  CONTENTS 


I.  Introduction:  Discussion  of  the  Problem. 

II.  Historical. 

III.  Theoretical  Consideration. 

IV.  Experimental. 

a.  Preparation  and  properties  of  some  alkaloidal  tartrates. 

b.  Determination  of  the  equilibrium  conditions  for  the  partition  of 

alkaloids  and  alkaloidal  salts  between  neutral  and  acid  aqueous 
solutions  and  an  immiscible  solvent  (chloroform  or  ether) . 

1 .  Extraction  of  a  neutral  or  acid  aqueous  alkaloidal  solution  with  an 

immiscible  solvent. 

2.  Extraction  of  the  solution  of  an  alkaloid  in  immiscible  solvent 

with  an  acid. 

c.  Calculation  of  the  extraction  factors  under  the  various  equilibrium 

conditions  examined,  as  well  as  those  reported  in  the  literature. 

V.  Discussion  of  Results. 

VI.  Summary. 


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♦ 


STUDIES  ON  THE  QUANTITATIVE  ESTIMATION  OF  ALKALOIDS  BY 
MEANS  OF  IMMISCIBLE  SOLVENTS. 

HARRY  F.  LEWIS. 

I.  INTRODUCTION  :  DISCUSSION  OF  THE  PROBLEM. 

One  of  the  oldest  and  most  widely  used  methods  of  alkaloidal  assay  is  based 
upon  the  general  principle  that  alkaloids  themselves  are  quite  insoluble  in  water 
and  soluble  in  organic  solvents,  while  their  salts  are  soluble  in  water  and  insoluble 
in  the  organic  solvents.  The  method  of  alkaloidal  assay  based  upon  this  principle 
is  known  as  the  “shaking  out”  process  familiar  through  its  connection  with  the 
Dragendorff1  method  of  plant  analysis  and  the  Stas-Otto2  poison  assay.  It  is 
assumed  that  the  alkaloidal  salt  is  practically  insoluble  in  organic  solvents  and  the 
alkaloid  insoluble  in  neutral  aqueous  solutions.  It  also  assumes  that  the  salt  is 
neither  hydrolyzed  by  the  aqueous  solvent  nor  decomposed  by  the  organic  solvent. 
Both  Dragendorff  and  Otto  certainly  realized  that  the  principles  were  not  absolute. 
Dragendorff  made  exception  to  the  rule  in  the  case  of  the  almost  quantitative 
removal  of  caffeine  and  the  removal  of  traces  of  veratrine  by  benzene  and  of 
theobromine,  colchicine,  papaverine,  narceine  and  traces  of  narcotine  by  chloroform 
from  acid  aqueous  solution  of  the  alkaloids.  Otto  recognized  the  fact  that  ether 
took  up  traces  of  colchicine,  papaverine,  narcotine,  veratrine  and  atropine  from 
their  acid  solution. 

In  most  alkaloidal  assays  of  this  type,  the  acid  aqueous  solution  obtained  by 
the  extraction  of  the  sample  with  dilute  acid  is  shaken  out  with  the  organic  solvent, 
in  order  to  remove  from  the  mixture  those  substances  which  might  later  appear 
with  the  alkaloid,  causing  inaccurate  results  in  the  assay.  Such  substances  are 
coloring  matter,  essential  oils,  bitter  principles,  tannins,  etc.  After  this  the  acid 
aqueous  solution  is  made  alkaline  and  shaken  out  with  more  immiscible  solvent, 
removing  the  alkaloid  in  more  or  less  pure  condition.  Purification  is  completed 
by  shaking  out  this  chloroform  or  ether  solution  with  acid,  making  the  acid  solution 
alkaline  and  shaking  opt  with  more  chloroform  or  ether.  This  is  done  several 
times.  Finally,  the  organic  solvent  is  removed  by  evaporation,  and  the  residue 
determined  by  direct  weight  or  by  dissolving  in  standard'  acid  and  titrating  the 
excess  with  standard  alkali. 

During  the  process,  several  sources  of  error  are  being  introduced.  In  the  first 
place,  the  alkaloidal  salt  may  be  slightly  soluble  in  the  organic  solvent.  There  is  also 
the  possibility  of  the  salt  being  hydrolyzed  by  the  water  present  into  free  alkaloid 
and  acid.  This  free  alkaloid  would  be  easily  soluble  in  the  organic  solvent.  There  are 
some  cases  known  where  the  organic  solvent  either  decomposes  the  alkaloid  or  else 
combines  with  it.  These  factors  may  cause  a  decrease  in  the  amount  of  alkaloid  in 
the  acid  solution  with  a  corresponding  decrease  in  the  total  alkaloid  at  the  end  of  the 
assay.  During  the  removal  of  the  alkaloid  from  an  alkaline  solution  by  extraction 
with  organic  solvent,  any  insolubility  of  the  alkaloid  in  the  solvent  and  solubility  in 
the  alkaline  solution  will  cause  low  results.  This  last,  however,  is  not  a  great  source 


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of  error,  except  in  the  extraction  of  certain  alkaloids  with  ether.  And  finally,  the 
shaking  out  of  the  alkaloidal  solution  in  organic  solvent  introduces  the  problem  of 
the  possible  insolubility  of  the  salt  formed  in  the  acid  solution  or,  if  not  its  insolu¬ 
bility,  its  slow  solubility.  This  is  very  apparent  in  the  case  of  the  salts  of  strychnine. 

It  is  the  purpose  of  this  work  to  obtain  such  results  as  will  describe  the 
partition  of  the  alkaloid  between  the  acid  layer  and  the  immiscible  solvent,  using 
different  acids  under  different  concentration  conditions.  In  order  to  obtain  more 
complete  data,  the  equilibrium  conditions  were  determined,  starting  with  an  acid 
solution  of  the  alkaloid  and,  as  well,  shaking  out  the  solution  of  the  alkaloid  in 
organic  solvent  with  an  acid.  Thus  it  is  hoped  that  the  following  conditions  might 
be  established  for  each  alkaloid : 

(a)  Which  salt  is  most  insoluble  in  chloroform  or  ether,  and  what  concen¬ 
tration  of  acid  is  most  favorable  to  this  condition. 

( b )  Which  acid,  and  in  what  concentration,  removes  the  alkaloid  most  com¬ 
pletely  from  its  solution  in  chloroform  or  ether. 

In  order  to  put  the  results  obtained  in  the  form  most  quickly  available,  a  new 
term,  that  of  extraction  factor,  has  been  introduced  and  the  factor  calculated  for 
the  different  sets  of  conditions  obtained  in  the  course  of  the  research.  By  extrac¬ 
tion  factor  is  meant  the  ratio  of  the  amount  of  alkaloid  in  the  layer  of  added 
solvent  to  the  amount  originally  present  in  the  first  solution.  For  practical  pur¬ 
poses,  this  would  be  a  far  better  value  to  have  than  that  of  the  partition  ratio  or 
the  sum  of  the  partition  ratios  for  the  different  alkaloidal  molecular  species  present. 
The  extraction  factor  shows  at  a  glance  the  completeness  of  the  extraction,  an 
indication  of  the  value  of  extraction  under  those  conditions.  The  partition  ratio 
tells  only  the  partition  of  one  molecular  species  between  two  layers  of  equal  volume, 
by  definition  of  the  term  partition  ratio. 

II.  HISTORICAL. 

Attention  was  first  called  to  the  quantitative  solution  of  the  problem  through 
an  article  published  by  Dr.  C.  Kippenberger3  in  1897.  In  this  paper  he  states 
clearly  the  possibilities  of  error  in  alkaloidal  estimation  through  hydrolysis  of  the 
salt  with  the  subsequent  solution  of  the  free  alkaloid.  He  suggests  the  use  of 
chloroform  or  chloroform  containing  a  little  alcohol  as  solvents. 

Three  years  later  Kippenberger4  published  a  second  paper,  in  which  he  en¬ 
deavored  to  establish  the  question  on  a  firmer  basis.  He  worked  with  the  alkaloids 
strychnine,  brucine,  atropine,  morphine,  aconitine,  veratrine,  papaverine,  narceine, 
codeine,  emetine,  pelletierine,  cocaine,  quinine,  narcotine,  coniine,  sparteine,  the- 
baine,  hyoscyamine,  daturine,  scopolamine  and  the  base  caffeine.  For  shaking 
out  he  used  chloroform  and  ether. 

The  action  of  the  salts  of  the  following  acids  was  studied :  Hydrochloric  acid, 
21.9  percent  HC1 ;  sulphuric  acid,  40.1  percent  H2S04 ;  tartaric  acid;  oxalic  acid. 
In  some  cases,  sodium  chloride  was  added  to  the  acid  solution  and  its  effect 
observed. 

The  alkaloid  was  dissolved  with  an  excess  of  acid  in  70  Cc.  of  water,  and  50 
Cc.  of  the  immiscible  solvent  added.  This  mixture  was  shaken  in  a  separatory 
funnel  for  about  three  minutes.  After  fully  clearing,  the  layers  were  separated 
and  the  chloroform  or  ether  layer  washed  with  a  few  Cc.  of  water.  The  organic 
solvent  was  then  evaporated  on  a  water-bath  and  the  residue,  alkaloid  plus  alka¬ 
loidal  salt,  dried  over  concentrated  sulphuric  acid.  The  amounts  of  alkaloid  and 
alkaloidal  salt  were  determined  in  the  following  manner ;  the  residue  was  dissolved 


AMERICAN  PHARMACEUTICAL  ASSOCIATION 


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in  an  excess  of  standard  acid  and  the  excess  acid  titrated  back  with  iL  standard 
alkali.  This  value  for  acid  neutralized  by  alkaloid  indicated  the  amount  of  free 
alkaloid  present  in  the  residue.  The  solution  was  then  made  alkaline  with  a  slight 
excess  of  sodium  hydroxide  and  extracted  again  with  chloroform.  The  amount  of 
total  alkaloid  was  obtained  by  evaporation  of  the  solvent  and  solution  of  the  residue 
in  standard  acid  with  titration  for  excess  acid  as  before.  Subtraction  of  the  first 
value,  that  of  the  free  alkaloid  from  the  second,  or  total  alkaloid  value  will  give 
the  amount  of  alkaloid  present  in  the  residue  as  salt. 

The  results  are  found  in  the  following  tables.  The  column  containing  the 
strength  of  acidity  was  compiled  by  the  authors  of  this  paper,  from  the  data  of 
Kippenberger. 

TABLE  I. 


Extraction  of  an  Alkaloid  by  Chloroform  from  Its  Solution  in  Hydrochloric  Acid 

(Kippenberger). 


Alkaloid  solution  in  70  Cc.  water. 


Cm. 

0.2  Strychnine 

0.2  Brucine _ 

0.2  Atropine. . 
0.2  Morphine. 
0.2  Aconitine. . 
0.2  Veratrine. . 
0.2  Codeine.  .  . 
0.2  Cocaine.  .  . 
0.2  Quinine. . . 


Amount 

Alkaloid. 

of  alkaloid  T 
in  50  Cc.  Indicator. 

Strength 
of  acid. 

Free.  S 

CHCU. 

0.0910  Azolitmin 
0.0798  Azolitmin 
0.0014  Azolitmin 

.  Azolitmin 

0.0971  Azolitmin 
0.0807  Azolitmin 
Trace  Azolitmin 
0.0021  Azolitmin 
Trace  Azolitmin 


0.15N 

0.0114 

0.075N 

0.0056 

0.075N 

0.075N 

0.03N 

0.0158 

0.075N 

0.0077 

0.03N 

0.015N 

0.03N 

0.0806 

0.0742 


0.0813 

0.0730 


TABLE  II. 

Extraction  of  an  Alkaloid  by  Chloroform  from  its  Solution  in  Sulphuric  Acid 

(Kippenberger). 


Alkaloid  solution  in  70  Cc.  water. 


Cm. 

0.2  Strychnine, 
0.2  Brucine.  .  . 
0.2  Atropine. . 
0.2  Morphine. 
0.2  Aconitine. . 


0.2  Veratrine. 
0.2  Codeine.  . 
0.2  Quinine.  . 


Amount 
of  alkaloid 
in  50  Cc. 

Indicator. 

Strength 
of  acid. 

Alkaloid. 

CHCU. 

Free.  Salt. 

Trace 

Azolitmin 

0.17N 

.  0.0020 

Azolitmin 

0.17N 

Azolitmin 

0.034N 

Azolitmin 

0.034N 

.  0.0120 

Azolitmin 

0.017N 

0.0120 

0.0064 

Azolitmin 

0.085N 

0.0064 

Trace 

Azolitmin 

0.255N 

Trace 

Azolitmin 

0.017N 

Azolitmin 

0.034N 

Azolitmin 

0.034N 

TABLE  III. 

Extraction  of  an  Alkaloid  by  Chloroform  from  Its  Solution  in  a  Mixture  of  Hydro¬ 
chloric  Acid  and  Sodium  Chloride  (Kippenberger). 


Alkaloid  solution  in  70  Cc.  water. 
Cm. 

0.2  Atropine,  14  Cc.  NaCl. . . . 
0.2  Atropine,  14  Cc.  NaCl.. .  . 

0.2  Quinine,  14  Cc.  NaCl _ 

0.2  Aconitine,  14  Cc.  NaCl. .  . 
0.2  Quinine . 


Amount 
of  alkaloid 
in  50  Cc. 
CHCU. 

Indicator. 

Strength 
of  acid. 

0.0192 

0.0149 

Azolitmin 

Azolitmin 

0.075N 

0.015N 

0.0100 

Haematoxylin 

0.03N 

0.2160 

Azolitmin 

0.017N 

0.0057 

Haematoxylin 

0.03N 

Alkaloid. 

Free.  Salt. 


.  Trace 

.  Trace 

0.0037  Acid  salt 

0.0063  Neutral  salt 
0.0306  0.1854 

0.004  Acid  salt 

0.0017  Neutral  salt 


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TABLE  IV. 

Extraction  of  an  Alkaloid  by  Chloroform  from  Its  Solution  in  Tartaric  Acid 

(Kippenberger). 


Alkaloid  solution  in  70  Cc.  water. 


Gm. 


Amount 
of  alkaloid 
in  50  Cc. 
CHCls. 


0.2  Strychnine. . . 
0.4  Tartaric  Acid , 

0.4  Brucine . 

0.4  Tartaric  Acid 


0.0020 

0.0032 


Strength  Alkaloid. 

Indicator.  of  acid. 

Free.  Salt. 


Azolitmin 

Azolitmin 


TABLE  V. 

Results  of  Shaking  Out  the  Acid  Alkaloidal  Solution  with  Ether,  Under  the  Same 
Conditions  as  Before  (Kippenberger). 

FROM  HYDROCHLORIC  ACID  SOLUTION. 

Ether  took  up : 


Narcotine . 0.0002  grammes. 

Caffeine . 0.0112  grammes,  as  free  caffeine. 


The  following  were  found  in  noticeable  traces : 

Aconitine,  narceine,  and  emetine. 

None  of  the  other  alkaloids  gave  up  a  trace  to  ether. 


FROM  SULPHURIC  ACID  SOLUTION. 

Ether  took  up : 

Caffeine . 0.0083  grammes  as  free  caffeine. 

The  following  were  found  in  noticeable  amounts : 

Aconitine,  papaverine,  narceine,  emetine  and  narcotine,  also  very  slight  traces  of  veratrine, 
strychnine,  and  codeine. 

THE  ADDITION  OF  SODIUM  CHLORIDE  TO  THE  SOLUTIONS  GAVE  THE  FOLLOWING  RESULTS  : 

(a)  From  hydrochloric  acid  in  noticeable  traces : 

Narcotine,  atropine,  and  quinine. 

( b )  From  sulphuric  acid  solution: 

Aconitine. 

Ether  removed  neither  brucine  nor  strychnine  from  tartaric  acid  solutions. 

In  1901,  Hans  Proelss5  gave  a  short  description  of  the  behavior  of  alkaloidal 
solutions  toward  different  solvents.  The  work  was  divided  in  two  parts :  The  first 
to  determine  the  best  solvent  for  the  alkaloids  as  a  class,  and  the  second,  the  best 
solvent  for  the  individual  alkaloids.  He  compared  the  relative  extractive  powers 
of  ether,  chloroform,  and  benzene,  and  also  mixtures  of  ether  and  chloroform, 
and  alcohol  and  chloroform,  for  the  alkaloids  picrotoxin,  veratrine,  strychnine, 
atropine,  codeine,  and  morphine.  His  method  consisted  in  dissolving  0.1  gramme 
of  alkaloid  in  50  Cc.  of  water  containing  a  few  drops  of  hydrochloric  acid.  After 
making  alkaline  with  sodium  carbonate,  the  aqueous  solution  was  extracted  three 
times  with  the  solvent.  He  states  that  constant  results  could  not  be  obtained  of 
sufficient  accuracy  to  b$  anything  more  than  comparative. 

1.  The  Best  Solvent  for  Alkaloids  in  General. 

Solvent.  Results. 

Ether . Very  good  with  colchicine,  brucine. 

Chloroform . Very  good  with  colchicine,  brucine,  digitalin,  veratrine,  atropine, 

strychnine. 

Chloroform  and  ether . Very  good  with  colchicine,  atropine,  veratrine,  picrotoxin. 

Chloroform  and  alcohol . Very  good  with  colchicine,  veratrine,  digitalin,  atropine,  codeine, 

morphine  plus  potassium  bicarbonate. 

Benzene . Very  good  with  colchicine,  strychnine,  atropine,  codeine,  picro¬ 

toxin. 


AMERICAN  PHARMACEUTICAL  ASSOCIATION 


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In  conclusion  he  states  that  the  best  shaking-out  liquid  for  alkaloids  in  general 
is  chloroform,  because  of  the  solubility  of  most  of  the  alkaloids  in  chloroform. 

2.  The  Best  Shaking-out  Liquid  for  the  Individual  Alkaloids. 


Alkaloids.  Results. 

Atropine . Any  solvent  satisfactory. 

Brucine . ' . Same  as  for  picrotoxin. 

Codeine . Alcohol  plus  chloroform,  benzene. 

Colchicine . Any  solvent  satisfactory. 

Morphine . Alcohol  plus  chloroform  from  potassium  carbonate  solution. 

Picrotoxin . .Ether,  chloroform  from  sodium  carbonate-ammonium  hydroxide 

solution. 

Strychnine . Chloroform,  alcohol  plus  chloroform,  benzene  from  sodium 

carbonate-ammoniacal  solution. 

Veratrine . Chloroform,  ether  plus  chloroform,  ether  and  benzene  from 

ammoniacal  solution. 


In  conclusion,  he  states  that  emulsions  form  easiest  with  benzene  and  least 
with  ether. 

Ed.  Springer,6  in  1902,  studied  the  effect  of  the  solvent  chloroform  on  the 
extraction  of  the  following  alkaloids :  Morphine,  coniine,  narcotine,  strychnine, 
quinine,  codeine,  veratrine,  and  cocaine  from  solutions  made  acid  with  sulphuric, 
phosphoric,  hydrochloric,  tartaric,  acetic,  oxalic  and  citric  acids. 

The  amount  of  alkaloid  in  the  residue  after  evaporation  of  chloroform  was 
determined  by  titration  in  the  same  way  that  Kippenberger  did.  For  some  reason, 
he  was  unable  to  obtain  check  results,  and  so  his  work  is  of  no  value  from  a 
quantitative  stand-point. 

The  following  are  his  results : 

Aconitine. — Aconitine  is  removed  as  the  salt  from  hydrochloric  acid  and  as 
the  pure  salt  in  traces  from  the  sulphuric  acid  solution. 

Atropine. — From  hydrochloric  acid,  traces  were  removed  as  the  salt;  from 
sulphuric  acid,  traces  as  the  free  alkaloid ;  traces  were  found  from  the  tartaric 
acid  solution,  also. 

Cocaine. — Some  alkaloid  is  extracted  from  sulphuric  and  hydrochloric  acid 
solutions,  where  the  acid  is  present  in  small  concentration. 

Codeine. — Codeine  is  not  found  in  the  chloroform  residues  from  extraction 
of  solutions  of  alkaloids  in  phosphoric,  tartaric,  oxalic,  citric,  and  sulphuric  acids, 
although  in  the  last  case  it  was  found  that  if  the  concentration  of  the  acid  was  low 
enough,  some  of  the  alkaloid  would  be  removed  as  the  free  base. 

Morphine,  Coniine,  and  Nicotine. — No  alkaloid  was  extracted  from  solutions 
made  acid  with  the  following  acids :  Hydro.chloric,  sulphuric  and  phosphoric. 

Narcotine. — Narcotine  is  removed  from  both  hydrochloric  and  sulphuric  acid 
solutions,  partly  as  base  and  partly  as  salt. 

Quinine. — No  alkaloid  is  removed  from  solutions  of  the  sulphate,  tartrate  or 
phosphate.  Some  quinine  is  removed  as  the  hydrochloride. 

Strychnine. — About  25  percent  was  removed  from  the  hydrochloric  acid  solu¬ 
tion  as  the  salt.  Slight  traces  were  removed  from  the  other  acid  solutions. 

Veratrine. — Veratrine  is  removed  in  traces  in  solutions  containing  small 
amounts  of  tartaric,  sulphuric,  and  citric  acids,  but  such  is  not  the  case  with  large 
excess  of  sulphuric  or  phosphoric  acids. 

From  this,  it  may  be  drawn  that  chloroform  is  a  “good  solvent’’  for  the  hydro¬ 
chloric  acid  salts  of  the  alkaloids.  The  solubility  of  the  hydrochlorides  is  so  great, 
in  fact,  that,  if  in  excess  of  acid,  the  salt  is  taken  over  completely  as  the  salt,  and 


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only  in  the  case  of  the  weak  base  narcotine  could  traces  of  the  free  alkaloid  be 
found  in  the  chloroform  extract. 

From  the  table,  one  would  expect  to  find  in  the  chloroform  extract  from  the 
sulphuric  acid  solution  in  the  Dragendorff  assay,  aconitine  and  narcotine,  as  well 
as  the  alkaloids  mentioned  by  Dragendorff  himself.  Strychnine,  veratrine  and 
atropine  might  also  be  found  in  small  amounts. 

In  1906,  Simmer7  published  an  important  paper  on  this  subject.  The  work 
was  divided  in  three  parts : 

1.  The  behavior  of  the  salts  of  the  common  alkaloids  toward  extraction  by 
chloroform  and  other  important  solvents. 

2.  The  appearance  of  decomposition  through  treatment  with  chloroform. 

3.  The  reducing  action  of  the  alkaloids. 

Simmer  prepared  an  aqueous  solution  of  the  alkaloidal  salt,  containing  0.2 
gramme  of  the  free  alkaloid  to  50  Cc.  of  solution,  or  0.4  percent  of  the  free  alkaloid. 
He  then  acidified  with  the  different  acids  until  he  obtained  the  desired  concentra¬ 
tions.  Simmer  neglected  to  state  definitely  the  amount  of  chloroform  used  in  the 
extraction,  but  the  general  tone  of  the  paper  would  lead  one  to  believe  that  he  used 
equal  amounts  of  chloroform  and  aqueous  solution.  These  were  mixed  and  the 
extraction  carried  on  for  an  hour.  At  the  end  of  that  time,  the  layers  were  sep¬ 
arated  and  the  chloroform  evaporated.  The  amount  of  free  alkaloid  and  alkaloidal 
salt  was  determined  in  the  residue  in  the  usual  manner. 

It  will  be  seen  from  the  tables  that  many  neutral  salts  are  extracted  by  both 
chloroform  and  benzene ;  this  is  especially  true  in  the  cases  of  the  salts  of  the  nitric 
and  halogen  acids. 

With  strychnine  hydrochloride,  the  least  amount  of  salt  is  extracted  from  the 
neutral  solution  and  the  most  from  the  solution  that  contains  a  10  percent  excess 
of  acid  ;  the  25  percent  acid  gives  up  less  alkaloid  than  the  10  percent  solution. 

The  behavior  of  the  weak  bases  colchicine,  caffeine,  narcotine,  papaverine,  and 
antipyrine  is  different.  In  strong  hydrochloric  acid  solution  of  colchicine,  there  is 
as  much  alkaloid  removed  by  the  chloroform  as  from  the  aqueous  solution.  The 
same  is  true  with  sulphuric  or  phosphoric  acid  solutions.  Caffeine,  thebaine  and 
narcotine  are  removed  from  weak  tartaric  acid  solutions  as  easily  as  from  stronger 
acid  solutions.  Papaverine,  narcotine,  and  thebaine  are  removed  simply  as  salts 
and  not  as  free  bases. 

TABLE  VI. 

Behavior  of  Neutral  and  Acidified  Alkaloidal  Salt  Solutions  Toward  Extraction 

with  Chloroform  (Simmer). 


Amount 

Strength, 

Grammes  alkaloid. 

Alkaloidal  salt. 

in  50  Gm. 
water. 

acid 

per  cent. 

Total. 

Free. 

Salt. 

Strychnine  hydrochloride . 

.  0.2377 

0.0 

0.0153 

0.0142 

0.0016 

0.2377 

0.1 

0.0083 

0 

0.0083 

0.2377 

1.0 

0.0250 

0 

0.0250 

0.2377 

10.0 

0.0559 

0 

0.0559 

0.2377 

25.0 

0.2330 

0 

0.2330 

Strychnine  hydrobromide . 

.  0.2480 

0.0 

0.0200 

0.0133 

0.0067 

0.2480 

0.1 

0.0167 

0 

0.0167 

0.2480 

1.0 

0.0350 

0 

0.0350 

Strychnine  hydriodide . 

.  0.2760 

0.0 

0.0560 

0.0250 

0.0317 

Strychnine  nitrate . 

.  0.2377 

0.0 

0.0283 

0.0233 

0.0050 

0.2377 

1.0 

0.0350 

0 

0.0350 

Strychnine  sulphate . 

Veratrine  hydrochloride . 

.  0.2610 

0.2610 

.  0.2110 

0.0 

1.0 

0.0 

Trace 

Trace 

0.0530 

0.0499 

0.0031 

0.2110 

0.1 

0.0327 

0 

0.0327 

0.2110 

10.0 

0.1248 

0 

0.1248 

AMERICAN  PHARMACEUTICAL  ASSOCIATION 


7 


TABLE  VI. — Continued. 


Amount 

Strength, 

Grammes  alkaloid. 

Alkaloidal  salt. 

in  50  Gm. 

acid 

water. 

per  cent. 

Total. 

Free. 

Salt. 

Veratrine  nitrate . 

.  0.2200 

0.0 

0.0405 

0.0405 

0 

0.2200 

1.0 

0.0811 

0 

0.0811 

Veratrine  sulphate . 

.  0.2150 

0.0 

0.0374 

0.0374 

0 

0.2150 

0.1 

Traces 

Veratrine  tartrate . 

.  0.2230 

0.1 

0.0842 

0.0842 

0 

0.2230 

2.0 

0.0155 

0.0155 

0 

0.2230 

5.0 

Traces 

Morphine  hydrochloride . 

.  0.2470 

0.0 

0.0045 

0.0045 

0 

0.2470 

0.1 

0 

0 

0 

0.2470 

5.0 

0 

0 

0 

Morphine  sulphate . 

.  0.2500 

0.0 

0.0037 

0.0037 

0 

0.2500 

0.1 

0 

0 

0 

Morphine  acetate . 

.  0.2630 

0.0 

0.0197 

0.0197 

0 

■Codeine  hydrochloride . 

.  0.2340 

0.0 

0.0371 

0.0371 

0 

0.2340 

0.1 

0.0015 

0 

0.0015 

0.2340 

10.0 

0.0079 

0 

0.0079 

Codeine  hydrobromide . 

.  0.2620 

0.0 

0.0126 

0.0126 

0 

0.2620 

0.1 

Traces 

0.2620 

10.0 

0.0110 

0 

0.0110 

0.2620 

25.0 

0.0079 

0 

0.0079 

Codeine  sulphate . 

.  0.2470 

0.0 

0.0276 

0.0276 

0 

0.2470 

0.1 

Traces 

Codeine  tartrate . 

.  0.2360 

0.1 

0.0110 

0.0110 

0 

Codeine  citrate . 

.  0.2480 

0.0 

0.0395 

0.0395 

0 

0.2480 

0.1 

0.0158 

0.0158 

0 

Cocaine  hydrochloride . 

.  0.2240 

0.0 

0.0490 

0.0490 

0 

0.2240 

0.1 

0.0037 

0.0015 

0.0022 

* 

0.2240 

1.0 

0.0045 

0 

0.0045 

0.2240 

10.0 

0.0075 

0 

0.0075 

Cocaine  sulphate . 

.  0.2640 

0.0 

0.0143 

0.0143 

0 

0.2640 

0.1 

Traces 

Cocaine  tartrate . 

.  0.2310 

0.0 

0.0543 

0.0543 

0 

0.2310 

0.1 

0.0528 

0.0528 

0 

0.2310 

1.0 

0.0332 

0.0332 

0 

0.2310 

5.0 

0.0015 

0.0015 

0 

Atropine  hydrochloride . 

.  0.2250 

0.0 

Traces  of  free  atropine. 

0.2250 

0.1 

Tratces  of  free  atropine. 

0.2250 

10.0 

0.0028 

0 

0.0028 

TABLE  VII. 

Behavior  of  Neutral  and  Acidified  Aklaloidal  Salt  Solutions  Toward  Extraction 

with  Benzene  (Simmer). 


Amount 

Strength, 

Grammes  alkaloid. 

Alkaloidal  salt. 

in  50  Gm. 

acid 

of  water. 

per  cent. 

Total. 

Free. 

Salt. 

Strychnine  hydrochloride . 

.  0.2377 

0.0 

0.0075 

0.0075 

0 

0.2377 

0.1 

0 

0 

0 

0.2377 

1.0 

0 

0 

0 

0.2377 

10.0 

Traces 

Strychnine  hydrobromide . 

.  0.2480 

0.0 

0.0033 

0.0033 

0 

0.2480 

0.1 

Traces 

Strychnine  hydriodide . 

.  0.2760 

0.0 

0.0033 

0.0033 

0 

Strychnine  sulphate . 

.  0.2610 

0.0 

0 

0 

0 

Strychnine  nitrate . 

.  0.2377 

0.1 

Traces 

Veratrine  sulphate . 

.  0.2150 

0.0 

Traces 

0.2150 

0.1 

Traces 

Codeine  hydrochloride . 

.  0.2340 

0.0 

0.0055 

0.0055 

0 

0.2340 

0.1 

0 

0 

0 

0.2340 

10.0 

0 

0 

0 

Codeine  hydrobromide . 

.  0.2620 

0.0 

0.0023 

0.0023 

0 

0.2620 

1.0 

0 

0 

0 

Codeine  sulphate . 

.  0.2470 

0.0 

0.0031 

0.0031 

0 

Codeine  citrate . 

.  0.2480 

0.0 

0.0023 

0.0023 

0 

8 


JOURNAL  OF  THE 


2.  THE  DECOMPOSING  POWER  OF  THE  ALKALOIDS  ON  CHLOROFORM. 

The  observation  had  been  made  by  many  authors  that  extraction  of  the  alkaloids 
with  chloroform  is  attended  with  a  decomposition  of  the  chloroform,  giving  rise 
to  free  hydrochloric  acid. 

In  order  to  determine  this,  Simmer  extracted  a  mixture  of  50  Gm.  of  water 
and  2  Gm.  of  finely  powdered  alkaloid  with  50  Gm.  of  chloroform  for  eight  hours. 
First  the  water  was  tested.  This  always  gave  an  opalescence  with  silver  nitrate, 
but  showed  itself  to  be  free  from  alkaloid,  except  in  the  few  cases  due  to  the  rela¬ 
tive  insolubility  of  the  alkaloid  in  chloroform.  The  chloroform  layer  was  then 
evaporated  and  the  residue  dissolved  in  water  containing  a  sufficient  amount  of 
sulphuric  acid.  Silver  nitrate  solution  was  then  added.  When  a  definite  precipitate 
was  observed,  this  was  filtered,  dissolved  in  ammonia  and  precipitated  again  with 
nitric  acid.  Then  the  pure  precipitate  was  filtered  in  a  Gooch  crucible  and  weighed. 


TABLE  VIII. 


Alkaloid,  2  Gm. 


AgCl  from  the 
chloroform 
layer. 


Corresponding  to — 


HC1. 

0.0009 

0.0033 


Alkaloid. 

0.0072 

0.0333 


0.0005 


0.0008 

0.0010 


0.0042 


0.0073 

0.0173 


Atropine .  0.0038 

Brucine .  0.0138 

Quinine . Traces 

Cinchonidine .  Traces 

Cinchonine .  Traces 

Cocaine .  0.0021 

Codeine .  Traces 

Morphine .  0 

Narcotine .  0 

Nicotine .  Traces 

Strychnine .  0 . 003 5 

Veratrine .  0.0043 

Thus  we  see  that  the  action  of  the  alkaloid  upon  the  chloroform  is  negligible, 
except  in  the  cases  of  brucine  and  veratrine. 

Marden  and  Elliott,8  in  1914,  published  a  paper  on  the  methods  of  extraction 
by  immiscible  solvents  from  the  point  of  view  of  the  distribution  ratios.  They 
shook  out  the  alkaloids  aconitine,  atropine,  codeine,  coniine,  morphine,  quinine, 
and  strychnine  with  the  solvents  chloroform  and  ether.  Ammonium  hydroxide 
was  used  to  make  the  acid  solution  alkaline. 

From  the  distribution  coefficient  and  a  certain  subsequent  algebraic  calculation, 
they  could  determine  the  number  of  extractions  necessary  to  remove  99.9  percent 
of  the  alkaloid.  The  distribution  ratio  (d)  is  indicated  by  the  expression. 

Concentration  in  10  Cc.  of  water  C  _  ^ 

Concentration  in  10  Cc.  of  non-aqueous  solvent  ^ 


The  algebraic  expression  for  the  calculation  of  the  number  of  shakings  neces¬ 
sary  for  an  extraction  is  indicated  by 


a 

e 


d 


where 


=  volume  of  the  aqueous  solvent. 

=  volume  of  non-aqueous  solvent. 

=  distribution  ratio. 

=  original  amount  of  material  to  be  extracted  in  the  aqueous  layer. 
=  amount  of  material  in  the  water  layer  after  n  extractions. 


In  the  system  aconitine,  ether  and  aqueous  ammoniacal  solution,  using  100  Cc. 
water,  5  Cc.  ammonium  hydroxide,  and  50  Cc.  of  ether,  the  following  result  was 
obtained,  d  —  0.140;  but  on  substituting  30  Cc.  of  chloroform  for  the  50  Cc.  of 
ether,  the  value  of  d  became  0.017. 


AMERICAN  PHARMACEUTICAL  ASSOCIATION 


9 


Atropine. — The  distribution  ratio  in  the  system  water  and  chloroform  was 
found  to  be  very  small  and  three  extractions  with  10  Cc.  of  chloroform  from  50 
Cc.  of  the  aqueous  solution  were  sufficient  to  remove  the  atropine. 

Codeine. — In  the  system,  100  Cc.  water,  5  Cc.  ammonium  hydroxide,  and  50 
Cc.  ether,  d  had  a  value  of  0.939.  If  30  Cc.  chloroform  were  substituted  for  the 
ether,  the  value  became  0.0067. 

Coniine. — Owing  to  the  volatility  of  the  coniine,  it  was  very  difficult  to  get  the 
partition  ratio. 

Morphine. — In  the  system,  saturated  aqueous  solution  of  potassium  carbonate 
and  a  mixture  of  methyl  alcohol  and  chloroform,  d  possessed  a  value  of  0.154,  with 
variations  from  0.200  to  0.127.  The  value  for  the  system,  100  Cc.  water,  contain¬ 
ing  35  Gm.  sodium  chloride,  and  45  Cc.  of  a  2:1  mixture  of  chloroform  and  ethyl 
alcohol  was  found  to  be  0.528. 

The  value  for  d  between  water  and  chloroform-amyl  alcohol  mixtures  was 
0.345. 

Quinine. — Between  water  made  alkaline  with  ammonium  hydroxide  and  chloro¬ 
form,  quinine  was  found  to  possess  such  a  low  distribution  coefficient  that  three 
washings  of  a  50  Cc.  aqueous  solution  with  10  Cc.  of  chloroform  were  found  to 
remove  all  of  the  alkaloid. 

Strychnine. — The  authors  determined  the  distribution  coefficients  for  systems 
containing  chloroform  alone  and  in  a  mixture  with  ether  in  order  to  see  which 
would  prove  more  efficient,  as  there  has  been  a  great  difference  of  usage. 

For  the  system,  100  Cc.  of  water,  2  Cc.  of  ammonium  hydroxide,  and  30  Cc. 
of  chloroform,  d  was  found  to  be  equal  to  0.003,  but  on  substituting  a  mixture  of 
1 :3  chloroform  and  ether,  the  value  0.087  was  obtained. 

Summary  of  the  Historical  Chapter. — In  looking  over  the  work  that  has 
been  published  on  the  subject  of  the  quantitative  estimation  of  the  alkaloids  by  the 
shaking-out  process,  sufficient  data  will  be  found  to  establish  the  equilibrium  con¬ 
ditions  of  the  systems,  alkaloidal  hydrochlorides  or  sulphates  between  their  acid 
solutions  and  chloroform  or  ether.  Results  are  lacking,  however,  which  will  show 
the  partition  of  alkaloidal  tartrates  between  tartaric  acid  and  those  solvents. 

In  addition  the  whole  subject  of  the  extraction  of  an  alkaloid  from  its  solu¬ 
tion  in  chloroform  by  an  acid  has  never  been  investigated.  If  equilibrium  is 
reached,  this  should  give  the  same  value  as  with  the  extraction  of  the  acid  salt 
solution  by  that  solvent.  In  practice,  it  takes  a  long  time  with  some  of  these  sys¬ 
tems  and  there  are  certain  other  factors  entering  in. 

III.  THEORETICAL  CONSIDERATION. 

In  an  acid  solution  of  a  neutral  alkaloidal  salt  the  following  equilibria 
are  established : 

(a)  The  alkaloidal  salt  is  in  equilibrium  with  the  free  alkaloid  and  acid,  due 
to  the  hydrolysis  of  the  salt,  and 

( b )  The  neutral  salt  and  acid  are  in  equilibrium  with  an  acid  salt.  It  is  pos¬ 
sible  that  more  than  one  acid  salt  may  be  formed,  in  which  case  there  will  be  as 
many  more  equilibrium  reactions  as  there  are  acid  salts  formed.  If  chloroform  is 
added  to  this  system,  and  the  mixture  shaken,  each  of  these  equilibria  may  be 
affected.  For  example,  the  mass  law  equation  for  the  hydrolysis  of  an  alkaloidal 
salt  is  expressed  by  the  following: 

^alkaloid  X  Cacid  —  U 


salt  X  GWater 


10 


JOURNAL  OF  THE 


where  k  is  the  mass  law  constant.  The  removal  of  one  of  the  constituents  will 
cause  a  resultant  shift  in  the  other  concentrations  in  order  that  k  may  remain  con¬ 
stant.  The  presence  of  a  great  excess  of  acid  will  drive  back  the  hydrolysis  by 
increasing  the  value  for  the  term  Cacid  with  the  resultant  decrease  in  value  for  the 
term  Calkaloid.  At  the  same  time,  solution  of  the  alkaloid  in  chloroform  will  cause 
a  decrease  in  the  value,  Calkaloid,  with  a  resultant  further  lowering  of  Csalt  in  order 
to  restore  equilibrium.  This  salt  whith  is  removed  is  hydrolyzed.  So  the  result 
of  the  removal  of  free  alkaloid  is  to  increase  the  hydrolysis.  Thus,  in  this  system 
at  equilibrium  the  conditions  existing  are  a  resultant  of  these  two  equilibria  which 
are  progressing  with  opposite  tendencies. 

To  approach  the  equilibrium  from  the  other  direction,  however,  introduces  a 
new  factor,  namely,  the  speed  of  solution  of  the  newly-formed  salt  in  acid  solution. 
As  the  two  immiscible  layers  are  being  shaken  together,  forming  an  intimate  mixt¬ 
ure  of  alkaloid  dissolved  in  chloroform  and  acid  in  the  water,  the  alkaloid  molecule 
in  the  chloroform  and  the  acid  molecule  in  the  aqueous  acid  liquid  meet  at  the 
junction  of  these  fine  drops  of  the  two  solutions,  and  combine. 

In  case’ the  acid  is  monobasic,  the  first  result  of  the  reaction  is  probably  the 
formation  of  a  neutral  salt.  In  an  excess  of  acid,  the  acid  salt  is  then  formed. 

With  the  dibasic  acids,  however,  such  as  tartaric  acid  or  sulphuric  acid,  the 
acid  salt  is  formed  first,  similarly  to  the  mechanism  of  the  neutralization  of  sul¬ 
phuric  acid  with  sodium  hydroxide.  As  more  alkaloid  combines,  there  is  a  gradual 
change  from  the  acid  salt  into  the  neutral  salt.  The  neutral  salt  in  many  cases 
seems  to  be  very  slowly  soluble  at  ordinary  temperatures,  although  it  goes  easily 
into  solution  at  boiling  temperature.  With  the  excess  of  acid,  however,  the  first 
acid  salt  is  formed,  which  in  some  cases  is  only  slightly  soluble  in  a  small  excess 
of  acid.  As  the  excess  of  acid  becomes  greater,  the  soluble  higher  acid  salts  are 
formed.  Thus  the  solution  in  acid  may  be  hastened  by  shaking  out  with  fresh 
portions  of  acid,  in  order  to  get  the  alkaloid  as  the  higher  acid  salt.  This  situation 
would  not  be  met  with  where  the  salt  solution  is  shaken  with  chloroform  or  ether, 
for  in  these  cases  the  salt  is  dissolved  at  a  much  higher  temperature  and  the 
solution  cooled. 

IV.  EXPERIMENTAL. 

(a)  Preparation  of  some  alkaloidal  tartrates  and  a  brief  description  of 
their  properties : 

The  neutral  salts  were  prepared  by  dissolving  the  alkaloids  in  an  aqueous 
acid  solution,  containing  equivalent  amounts  of  tartaric  acid  in  a  large  excess  of 
water,  at  the  boiling  temperature.  In  the  excess  of  hot  water,  the  acid  salt  which 
forms  first  stays  in  solution  and  the  remainder  of  the  alkaloid  completely  neutralizes 
it.  On  cooling  the  solution  slowly,  the  neutral  salt  comes  out  in  beautiful  crystals. 
In  one  or  two  cases  it  was  necessary  to  evaporate  some  of  the  solvent  water  in 
order  to  get  the  right  concentration  for  crystallization. 

The  mon-acid  salt  may  be  prepared  by  dissolving  the  alkaloid  in  a  slight  excess 
of  acid,  in  a  small  quantity  of  hot  water.  On  cooling  the  crystals  of  the  acid  salt 
will  come  out. 

These  salts  are  further  purified  by  crystallization  from  water  several  times. 

In  this  way  the  crystalline  salts  of  brucine,  cinchonine,  cinchonidine,  quinine, 
morphine,  and  strychnine  were  prepared.  The  alkaloids  aconitine,  atropine, 
cocaine,  codeine,  and  veratrine  were  obtained  in  the  form  of  tartrates  for  further 
investigation  by  simply  dissolving  the  alkaloids  in  the  proper  concentration  of  acid, 
as  their  tartrate  salts  were  amorphous. 


AMERICAN  PHARMACEUTICAL  ASSOCIATION 


11 


The  neutral  salts  are  characterized  as  follows : 

(The  amount  of  alkaloid  present  represents  the  percent  alkaloid  in  the 

anhydrous  salt.) 

Strychnine: 

M.  P.  226°-22 7°,  browning  at  215°. 

Crystalline  form:  beautiful  white  rosettes. 

Analysis :  81.68  percent  strychnine. 

15.00  percent  water. 

Theoretical  for  (C21H22N202)2.C4H606.8H20 : 

81.66  percent  strychnine. 

15.20  percent  water. 

Brucine: 

M.  P.  236°-237°,  with  decomposition;  browns  at  210°. 

Crystalline  form:  white  cubes. 

Analysis :  83.2  percent  brucine. 

9.1  percent  water. 

Theoretical  for  (C23H26N204)2.C4H606.5H20 : 

83.7  percent  brucine. 

8.8  percent  water. 

Quinine: 

M.  P.  199°,  with  browning. 

Crystalline  form :  fine  white  needles. 

Analysis :  81.28  percent  quinine. 

2.56  percent  water. 

Theoretical  for  (C20H24N2O2)2.C4H6O6.H2O : 

81.20  percent  quinine. 

2.3  percent  water. 

Cinchonidine : 

M.  P.  230°-231°  with  decomposition;  browns  at  218°. 

Crystalline  form  :  long  white  needles. 

Analysis  :  79.68  percent  cinchonidine. 

4.60  percent  water. 

Theoretical  for  (C19H22N20)2.C4H6062H20 : 

79.69  percent  cinchonidine. 

4.64  percent  water. 

Cinchonine : 

M.  P.  190°,  without  either  decomposition  or  browning. 

Crystalline  form :  short  white  needles. 

Analysis :  79.76  percent  cinchonine. 

2.8  percent  water. 

Theoretical  for  (C10H22N2O)2.C4H6O6.H2O : 

79.69  percent  cinchonine. 

2.4  percent  water. 

The  water  of  crystallization  was  determined  by  weighing  the  sample,  heating 
at  110°  to  constant  weight,  and  then  dissolving  the  anhydrous  salt  in  water.  The 
solution  was  made  alkaline  and  extracted  twice  with  an  excess  of  chloroform.  The 
chloroform  was  evaporated  and  the  residue  heated  to  constant  weight.  The  value 
obtained  was  that  of  the  weight  of  the  alkaloid  in  the  sample  of  salt  taken.  From 


12 


JOURNAL  OF  THE 


the  value  of  alkaloid  and  that  of  water  of  crystallization  was  calculated  the  formula 
of  the  salt.  The  one  exception  in  this  procedure  was  in  the  case  of  brucine  where 
the  residue  from  the  chloroform  extraction  of  the  alkaline  brucine  solution  was 
dissolved  in  standard  acid  and  the  excess  acid  titrated  back  with  standard  alkali. 

The  acid  salts  were  analyzed  in  the  same  manner. 

( b )  Determination  of  the  equilibrium  conditions  for  the  partition  of  the  alka¬ 
loids  and  alkaloidal  salts  between  aqueous  neutral  and  acid  solutions  and  an  immis¬ 
cible  solvent  (chloroform  or  ether)  : 

1.  Extraction  of  the  neutral  or  acid  aqueous  alkaloidal  solution  with  chloroform 
and  ether : 

0.2  Gm.  of  the  neutral  alkaloidal  salt  was  dissolved  in  25  Cc.  of  the  aqueous  acid 
solution  of  a  definite  concentration.  To  this  were  added  20  Cc.  of  chloroform  or 
ether  and  the  mixture  was  shaken  in  a  Jena  Erlenmeyer  flask  for  two  hours  and 
a  half,  at  a  temperature  of  25°.  The  shaking  was  carried  out  in  a  water  thermostat, 
accurate  to  within  a  tenth  of  a  degree.  The  time  of  shaking  was  chosen  after 
experiments  were  carried  out  to  determine  the  time  required  for  the  reaction  to 
come  to  equilibrium.  It  was  found  that  in  the  case  of  strychnine  tartrate  only  half 
this  time  was  required.  When  that  time  had  elapsed,  the  flasks  were  removed, 
the  layers  at  once  separated,  and  the  chloroform  or  ether  layer  put  in  a  small 
separatory  funnel.  After  standing  for  about  10  minutes  in  order  to  make  a  clear 
separation,  10  Cc.  of  the  chloroform  solution  were  measured  into  a  porcelain 
casserole,  and  the  chloroform  evaporated  on  a  steam-bath.  The  residue  was  taken 
up  in  10  Cc.  of  sulphuric  acid,  and  the  excess  acid  titrated  back  with  standard 
•go-  potassium  hydroxide.  Such  indicators  were  used  as  would  give  the  most 
accurate  results  for  the  individual  alkaloids.  The  selection  of  indicator  was 
made  after  reference  to  Kippenberger’s  article.  The  value  obtained  in  this  way 
gave  the  amount  of  free  alkaloid  present  in  the  residue.  The  neutral  solution  was 
made  alkaline  and  extracted  with  chloroform.  After  separation,  the  solvent 
was  evaporated  and  the  residue  again  taken  up  in  standard  acid  and  titrated  back 
with  standard  alkali.  This  gave  the  value  for  the  total  alkaloid.  By  subtracting 
the  first  value  from  the  second,  the  amount  of  alkaloid  present,  combined  with 
acid  in  the  form  of  salt,  was  obtained. 

With  morphine,  a  slightly  different  procedure  was  carried  out.  In  determining 
the  amount  of  total  alkaloid,  the  neutral  solution  after  the  first  titration  was  made 
alkaline  with  ammonium  hydroxide,  since  sodium  and  potassium  hydroxide  form 
salts  with  morphine  which  are  soluble  in  alkaline  solution.  The  alkaline  solution 
was  then  extracted  with  amyl  alcohol,  until  it  showed  the  absence  of  alkaloid,  amyl 
alcohol  being  the  best  solvent  for  morphine  which  will  answer  the  purpose. 

The  solutions  of  the  neutral  salts  were  of  the  following  acid  strengths  :  Neutral, 
■sAT’TT'  The  equilibrium  conditions  were  determined  for  the  tartrate  salts 
of  the  alkaloids  aconitine,  atropine,  cinchonidine,  cinchonine,  cocaine,  codeine, 
quinine,  morphine,  strychnine  and  veratrine,  in  tartaric  acid  solutions.  The  equi¬ 
librium  conditions  for  the  solutions  of  alkaloidal  sulphates  in  sulphuric  acid  and 
hydrochlorides  in  hydrochloric  acid  were  worked  out  with  the  idea  of  supplementing 
and  adding  to  those  values  obtained  by  Kippenberger  and  Simmer.  Table  IX 
gives  the  results  of  the  extraction  of  the  salt  solution  by  chloroform,  and  Table  X, 
the  values  obtained  by  the  extraction  with  ether. 

2.  Conditions  at  equilibrium  in  systems  in  which  the  alkaloid  is  being  removed 
from  its  chloroform  solution  by  an  acid. 


* 


AMERICAN  PHARMACEUTICAL  ASSOCIATION 


13 


TABLE  IX. 

Grammes  alkaloid  in  20  Cc. 


Alkaloid. 

Acid. 

Strength. 

Total. 

chloroform. 

Free. 

Salt. 

Indicator. 

Strychnine . 

. .  .  HTr 

N/2 

0 

0 

0 

Azolitmin 

HTr 

N/4 

0 

0 

0 

Azolitmin 

HTr 

N/8 

0 

0 

0 

Azolitmin 

HTr 

Neut. 

0.0120 

0.0104 

0.0016 

Azolitmin 

Sulph. 

N/2 

0 

0 

0 

Azolitmin 

, 

Sulph. 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

N/50 

0 

0 

0 

Azolitmin 

Sulph. 

Neut. 

0.0127 

0.0127 

0 

Azolitmin 

HC1 

N/2 

0.0522 

0 

0.0522 

Azolitmin 

HC1 

N/4 

0.0424 

0 

0.0424 

Azolitmin 

HC1 

N/8 

0.0394 

0 

0.0394 

Azolitmin 

Neut. 

0.0085 

0.0081 

0.0005 

Azolitmin 

Brucine . 

. .  .  HTr 

N/2 

0 

0 

0 

Azolitmin 

HTr 

N/4 

0 

0 

0 

Azolitmin 

HTr 

N/8 

0.0026 

0.0026 

0 

Azolitmin 

HTr 

Neut. 

0.0076 

0.0076 

0 

Azolitmin 

Sulph. 

N/2 

0 

0 

0 

Azolitmin 

Sulph. 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

Neut. 

0.0143 

0.0143 

0 

Azolitmin 

Cinchonidine . 

.  .  .  HTr 

N/2 

0.0012 

0.0012 

0 

Azolitmin 

HTr 

N/4 

0.0024 

0.0024 

0 

Azolitmin 

HTr 

N/8 

0.0018 

0.0018 

0 

Azolitmin 

HTr 

’Neut. 

0.0024 

0.0024 

0 

Azolitmin 

Sulph. 

N/2 

0 

0 

0 

Azolitmin 

Sulph. 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

Neut. 

0.0086 

0.0086 

0 

Azolitmin 

Cinchonine . 

.  .  .  HTr 

N/2 

0 

0 

0 

Azolitmin 

HTr 

N/4 

0 

0 

0 

Azolitmin 

HTr 

N/8 

0 

0 

0 

Azolitmin 

HTr 

Neut. 

0.0016 

0 

0.0016 

Azolitmin 

Caffeine . 

N/2 

0.1928 

0.1928 

0 

weight  of  residue 

Sulph. 

N/4 

0.1930 

0.1930 

0 

weight  of  residue 

Sulph. 

N/8 

0.1300 

0.1300 

0 

weight  of  residue 

Sulph. 

Neut. 

0.1032 

0.1032 

0 

weight  of  residue 

Cocaine . 

...  HC1 

N/2 

0 

0 

o  . 

Iodeosin 

HC1 

N/4 

0 

0 

0 

Iodeosin 

HC1 

N/8 

0.0432 

0.0432 

0 

Iodeosin 

HC1 

Neut. 

0.0432 

0 

0.0432 

Iodeosin 

Codeine . 

.  .  .  HTr 

N/2 

0 

0 

0 

Azolitmin 

HTr 

N/4 

0 

0 

0 

Azolitmin 

HTr 

N/8 

0.0018 

0.0018 

0 

Azolitmin 

HTr 

Neut. 

0.0046 

0.0046 

0 

Azolitmin 

Quinine . 

. .  .  HTr 

N/2 

0.0014 

0 

0.0014 

Azolitmin 

HTr 

N/4 

0.0028 

0.0014 

0.0014 

Azolitmin 

HTr  N/8  0.0018 

Neutral  salt  but  slightly 

0.0014  0.0014 

soluble  in  water. 

Azolitmin 

Sulph. 

N/2 

0 

0 

0 

Azolitmin 

Sulph. 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

Neut. 

0 

0 

0 

Azolitmin 

Aconitine . 

.  .  .  HTr 

N/2 

0 

0 

0 

Cochineal 

HTr 

N/4 

0.0537 

0 

0.0537 

Cochineal 

HTr 

N/8 

0.0099 

0 

0.0099 

Cochineal 

HTr 

Neut. 

0.0236 

0.0136 

0.0099 

Cochineal 

Atropine . 

.  .  .  HTr 

N/2 

0 

0 

0 

Cochineal 

HTr 

N/4 

0.0036 

0.0036 

0 

Cochineal 

HTr 

N/8 

0.0038 

0.0010 

0.0028 

Cochineal 

HTr 

Neut. 

0.0018 

0.0018 

0 

Cochineal 

Morphine . 

. .  .  HTr 

N/2 

0 

0 

0 

Cochineal 

HTr 

N/4 

0 

0 

0 

Cochineal 

HTr 

N/8 

0 

0 

0 

Cochineal 

HTr 

Neut. 

0 

0 

0 

Cochineal 

Veratrine . 

. .  .  HTr 

N/2 

0.0049 

0.0049 

0 

Cochineal 

HTr 

N/4 

0.0116 

0.0116 

0 

Cochineal 

HTr 

N/8 

0.0112 

0.0112 

0 

Cochineal 

HTr 

Neut. 

0.0294 

0.0294 

0 

Cochineal 

14 


JOURNAL  OF  THE 


TABLE  X1. 


Grammes  alkaloid  in  20  Cc.  ether. 


Alkaloid. 

Acid. 

Strength. 

Total. 

Free. 

Salt. 

Indicator, 

Strychnine . 

. . . .  HTr 

N/2 

0 

0 

0 

Azolitmin 

HTr 

N/4 

0 

0 

0 

Azolitmin 

HTr 

N/8 

0 

0 

0 

Azolitmin 

HTr 

Neut. 

0 

0 

0 

Azolitmin 

Sulph. 

N/2 

0 

0 

0 

Azolitmin 

Sulph. 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

Neut. 

0.0027 

0.8027 

0.8027 

Azolitmin 

Brucine . 

. .  .  HTr 

N/2 

0 

0 

0 

Azolitmin 

HTr 

N/4 

0 

0 

0 

Azolitmin 

HTr 

N/8 

0.0040 

? 

? 

Azolitmin 

HTr 

Neut. 

0.0032 

0.0032 

0 

Azolitmin 

Sulph. 

N/2 

0 

0 

0 

Azolitmin 

Sulph. 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

Neut. 

0 

0 

0 

Azolitmin 

Cinchonidine . 

. .  .  HTr 

N/2 

0.0018 

? 

? 

Azolitmin 

HTr 

N/4 

0.0018 

? 

? 

Azolitmin 

HTr 

N/8 

0 

6 

0 

Azolitmin 

HTr 

Neut. 

0.0024 

0.0012 

0.0012 

Azolitmin 

Sulph. 

N/2 

0 

0 

0 

Azolitmin 

Sulph. 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

Neut. 

0.0040 

0.0040 

0 

Azolitmin 

Cinchonine . 

.  .  .  HTr 

N/2 

0 

0 

0 

Azolitmin 

HTr 

N/4 

0 

0 

0 

Azolitmin 

HTr 

N/8 

0.0014 

? 

? 

Azolitmin 

• 

HTr 

Neut. 

0.0023 

0.0023 

6 

Azolitmin 

Uodeine . 

.  .  .  HTr 

N/2 

0 

0 

0 

Azolitmin 

HTr 

N/4 

0 

0 

0 

Azolitmin 

HTr 

N/8 

0 

0 

0 

Azolitmin 

HTr 

Neut. 

0 

0 

0 

Azolitmin 

Sulph. 

N/2 

0 

0 

0 

Azolitmin 

Sulph. 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

N/8 

0.0023 

0 

0.0023 

Azolitmin 

Sulph. 

Neut. 

0 

0 

0 

Azolitmin 

Aconitine . 

. . .  HTr 

N/2 

0 

0 

0 

Cochineal 

HTr 

N/4 

0 

0 

0 

Cochineal 

HTr 

N/8 

0.0052 

? 

? 

Cochineal 

HTr 

Neut. 

0.0060 

6 

0.0060 

Cochineal 

Atropine . 

. .  .  HTr 

N/2 

0 

0 

0 

Cochineal 

HTr 

N/4 

0.0011 

? 

? 

Cochineal 

HTr 

N/8 

0.0014 

? 

? 

Cochineal 

HTr 

Neut. 

0.0021 

6 

6.0021 

Cochineal 

Morphine . 

. .  .  HTr 

N/2 

0 

0 

0 

Cochineal 

HTr 

N/4 

0 

0 

0 

Cochineal 

HTr 

N/8 

0 

0 

0 

Cochineal 

HTr 

Neut. 

0 

0 

0 

Cochineal 

Sulph. 

N/2 

0 

0 

0 

Cochineal 

Sulph. 

N/4 

0 

0 

0 

Cochineal 

Sulph. 

N/8 

0.0011 

0.0011 

0 

Cochineal 

Sulph. 

Neut. 

0.0019 

0.0019 

0 

Cochineal 

Quinine . 

.  .  .  HTr 

N/2 

0 

0 

0 

Azolitmin 

HTr 

N/4 

0 

0 

0 

Azolitmin 

HTr 

N/8 

0.0014 

? 

? 

Azolitmin 

Sulph. 

N/2 

0 

6 

6 

Azolitmin 

Sulph. 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

Neut. 

0 

0 

0 

Azolitmin 

Veratrine . 

. . .  HTr 

N/2 

0 

0 

0 

Cochineal 

HTr 

N/4 

0 

0 

0 

Cochineal 

HTr 

N/8 

0 

0 

0 

Cochineal 

HTr 

Neut. 

0.0024 

0.0024 

0 

Cochineal 

1  Owing  to  the  solubility  of  tartaric  acid  in  ether,  it  is  impossible  to  say  whether  the  salt  is 
present  in  the  ether  in  the  free  state  or  as  salt,  in  the  extraction  from  acid  solution. 


AMERICAN  PHARMACEUTICAL  ASSOCIATION 


15 


0.2  Gm.  of  the  alkaloid  were  dissolved  in  20  Cc.  of  chloroform  and  25  Cc.  of  the 
required  concentration  acid  added.  The  mixture  was  shaken  for  two  hours  and  a 
half,  in  the  same  manner  as  was  the  previous  case,  at  25°.  After  separation  of 
the  two  layers,  the  amount  of  alkaloid  and  alkaloidal  salt  in  the  chloroform  layer 
was  determined.  The  results  are  tabulated  in  Table  XI.  Owing  to  the  insolubility 
of  some  of  the  alkaloids  in  ether,  values  were  not  always  obtained  for  the  use  of  this 
solvent.  The  chloroform  solutions  of  the  alkaloids  were  shaken  out  with  sulphuric, 
hydrochloric  and  tartaric  acids  of  the  concentrations,-^,™,-^.  In  the  case  of 
strychnine,  even  more  dilute  acid  solutions  were  used.  In  those  cases  where  the 
salt  formed  is  but  slowly  soluble  in  the  acids,  experiments  were  made  to  determine 
how  many  shakings  would  more  quickly  dissolve  the  salt,  and  what  strength  acid 
would  be  best. 


Alkaloid. 

Aconitine . . 

TABLE  XI. 

NatUrfcid°IUme*  Strength. 
Cc. 

....  HTr  25  N/2 

Grammes  alkaloid  in 
chloroform. 

Total.  Free. 

0  0 

20  Cc. 

Salt. 

0 

Indicator. 

Cochineal 

HTr 

50 

N/4 

0 

0 

0 

Cochineal 

HTr 

50 

N/8 

0 

0 

0 

Cochineal 

HC1 

25 

N/2 

0.0342 

0 

0.0342 

Cochineal 

HC1 

25 

N/4 

0.0257 

0 

0.0257 

Cochineal 

HC1 

25 

N/8 

0.0146 

0 

0.0146 

Cochineal 

Atropine . 

HTr 

25 

N/4 

0.0146 

0.0010 

0 

Cochineal 

HTr 

25 

N/8 

0.0010 

0.0010 

0 

Cochineal 

Brucine . 

.  . .  .  HTr 

25 

N/2 

0 

0 

0 

Azolitmin 

HTr 

25 

N/4 

0 

0 

0 

Azolitmin 

HTr 

25 

N/8 

0.0014 

0.0014 

0 

Azolitmin 

HTr 

35 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/2 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/4 

0.0008 

0.0008 

0 

Azolitmin 

Sulph. 

25 

N/8 

0.0012 

0.0012 

0 

Azolitmin 

HC1 

25 

N/2 

0.0768 

0 

0.0768 

Azolitmin 

HC1 

25 

N/4 

0.0583 

0 

0.0583 

Azolitmin 

HC1 

25 

N/8 

0.0445 

0 

0.0445 

Azolitmin 

Cinchonidine . . 

. . .  .  HTr 

25 

N/2 

0 

0 

0 

Azolitmin 

HTr 

50 

N/4 

0 

0 

0 

Azolitmin 

HTr 

50 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/2 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/8 

0.0012 

0.0012 

0 

Azolitmin 

HC1 

25 

N/2 

0 

0 

0 

Azolitmin 

HC1 

25 

N/4 

0 

0 

0 

Azolitmin 

HC1 

25 

N/8 

0 

0 

0 

Azolitmin 

Cinchonine . 

HTr 

25 

N/2 

0 

0 

0 

Azolitmin 

HTr 

25 

N/4 

0 

0 

0 

Azolitmin 

HTr 

25 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/2 

0 

0 

0 

Azolitmin 

Sul'ph. 

25 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/8 

0.0011 

0.0011 

0 

Azolitmin 

HC1 

25 

N/2 

0 

0 

0 

Azolitmin 

HC1 

25 

N/4 

0 

0 

0 

Azolitmin 

HC1 

25 

N/8 

0 

0 

0 

Azolitmin 

Cocaine . 

. . .  .  HTr 

25 

N/2 

0 

0 

0 

Cochineal 

HTr 

25 

N/4 

0 

0 

0 

Cochineal 

HTr 

25 

N/8 

0.0017 

0.0017 

0 

Cochineal 

Sulph. 

25 

N/2 

0 

0 

0 

Cochineal 

Sulph. 

25 

N/4 

0 

0 

0 

Cochineal 

Sulph. 

25 

N/8 

0 

0 

0 

Cochineal 

HC1 

25 

N/2 

0 

0 

0 

Cochineal 

HC1 

25 

N/4 

0 

0 

0 

Cochineal 

HC1 

25 

N/8 

0 

0 

0 

Cochineal 

16 


JOURNAL  OF  THE 


TABLE  XI. — Continued. 


Grammes  alkaloid  in 

20  Cc. 

Alkaloid. 

Nature,  volume, 
acid. 

Cc. 

Strength. 

Total. 

chloroform. 

Free. 

Salt. 

Indicator. 

Codeine . 

....  HTr 

25 

N/2 

0 

0 

0 

Azolitmin 

HTr 

25 

N/4 

0 

0 

0 

Azolitmin 

HTr 

25 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/2 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/8 

0 

0 

0 

Azolitmin 

HC1 

25 

N/2 

0 

0 

0 

Azolitmin 

HC1 

25 

N/4 

0 

0 

0 

Azolitmin 

HC1 

25 

N/8 

0 

0 

0 

Azolitmin 

Quinine . 

...  HTr 

25 

N/2 

0 

0 

0 

Azolitmin 

HTr 

25 

N/4 

0 

0 

0 

Azolitmin 

HTr 

25 

N/8 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/2 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/4 

0 

0 

0 

Azolitmin 

Sulph. 

25 

N/8 

0 

0 

0 

Azolitmin 

HC1 

25 

N/2 

0  ' 

0 

0 

Azolitmin 

HC1 

25 

N/4 

0 

0 

0 

Azolitmin 

HC1 

25 

N/8 

0 

0 

0 

Azolitmin 

Strychnine . 

. . .  HTr 

50 

4N 

0 

0 

0 

Azolitmin 

HTr 

100 

2N 

0 

0 

0 

Azolitmin 

HTr 

100 

N 

0.0011 

0 

0.0011 

Azolitmin 

HTr 

100 

N/2 

0.0011 

0 

0.0011 

Azolitmin 

HTr 

95 

N/4 

0.0011 

0 

0.0011 

Azolitmin 

HTr 

75 

N/8 

0.0011 

0 

0.0011 

Azolitmin 

HTr 

75 

N/12 

0.0029 

0 

0.0029 

Azolitmin 

HTr 

25 

N/25 

0.0125 

0 

0.0125 

Azolitmin 

HC1 

25 

N/2 

0.0202 

0 

0.0202 

Azolitmin 

HC1 

25 

N/4 

0.0250 

0 

0.0250 

Azolitmin 

HC1 

25 

N/8 

0.0202 

0 

0.0202 

Azolitmin 

Veratrine . 

HTr 

25 

N/2 

0.0020 

0.0020 

0.0020 

Cochineal 

HTr 

25 

N/4 

0.0040 

0.0040 

0 

Cochineal 

HTr 

25 

N/8 

0 

0 

0 

Cochineal 

Sulph. 

25 

N/2 

0 

0 

0 

Cochineal 

Sulph. 

25 

N/4 

0 

0 

0 

Cochineal 

Sulph. 

25 

N/8 

0 

0 

0 

Cochineal 

HC1 

25 

N/2 

0.07*0 

0 

0.0740 

Cochineal 

HC1 

25 

N/4 

0.0516 

0 

0  0516 

Cochineal 

HC1 

25 

N/8 

0.0426 

0 

0.0426 

Cochineal 

(c)  Calculation  of  the  extraction  factors  under  the  various  equilibrium  con¬ 
ditions  examined,  as  well  as  those  reported  in  the  literature : 

The  extraction  factor  is  simply  the  ratio  of  the  amount  of  alkaloid  found  in 
the  layer  of  the  added  solvent  to  the  amount  originally  present  in  the  first  solution, 
regardless  of  the  volumes  of  the  two  solutions.  This  gives  an  excellent  idea  of 
the  efficiency  of  the  different  sets  of  extraction  conditions. 

Table  XII  contains  the  data  and  values  for  the  extraction  factors  for  the  alka- 
loidal  tartrates  between  tartaric  acid  and  chloroform.  In  Table  XIII  will  be  found 
similar  values  where  ether  has  been  used  as  the  solvent.  The  extraction  factors 
for  the  sulphates  between  sulphuric  acid  and  chloroform  and  of  the  hydrochlorides 
between  hydrochloric  acid  and  chloroform  are  found  in  Tables  XIV  and  XV,  re¬ 
spectively.  Table  XVI  contains  the  values,  using  ether  for  the  solvent,  for  the 
sulphates. 

The  extraction  factors  for  the  extraction  of  the  alkaloids  from  their  chloroform 
solutions,  by  tartaric,  sulphuric  and  hydrochloric  acids,  will  be  found  in 
Table  XVII. 


AMERICAN  PHARMACEUTICAL  ASSOCIATION 


17 


TABLE  XII. 


Alkaloid. 
Strychnine . 

Brucine . 

Cinchonidine.  .  . 

Cinchonine . 

Quinine . 

Aconitine . 

Atropine . 

Codeine . 

Morphine . 

Yeratrine . •.  . 

Alkaloid. 
Strychnine . 

Brucine . 

Morphine . 

Cinchonidine.  .  . 


Acid. 

Strength. 

Chloroform. 

Volume.  Alkaloid. 

Acid 

volume. 

Original 

total 

alkaloid. 

Factor. 

HTr 

N/2 

20 

0 

25 

0.1650 

0 

HTr 

N/4 

20 

0 

25 

0.1650 

0 

HTr 

N/8 

20 

0.0104 

25 

0.1650 

0.0634 

HTr 

Neut. 

20 

0.0126 

25 

0.1650 

0.0768 

HTr 

N/2 

20 

0 

25 

0.1680 

0 

HTr 

N/4 

20 

0 

25 

0.1680 

0 

HTr 

N/8 

20 

0.0026 

25 

0.1680 

0.0154 

HTr 

Neut. 

20 

0.0076 

25 

0.1680 

0.0453 

HTr 

N/2 

20 

0.0012 

25 

0.1595 

0.0076 

HTr 

N/4 

20 

0.0024 

25 

0.1595 

0.0153 

HTr 

N/8 

20 

0.0018 

25 

0.1595 

0.0114 

HTr 

Neut. 

20 

0.0024 

25 

0.1595 

0.0153 

HTr 

N/2 

20 

0 

25 

0.1595 

0 

HTr 

N/4 

20 

0 

25 

0.1595 

0 

HTr 

N/8 

20 

0 

25 

0.1595 

0 

HTr 

Neut. 

20 

0.0016 

25 

0.1595 

0.0100 

HTr 

N/2 

20 

0.0014 

25 

0.1625 

0.0086 

HTr 

N/4 

20 

0.0028 

25 

0.1625 

0.0172 

HTr 

N/8 

20 

0.0028 

25 

0.1625 

0.0172 

HTr 

N/2 

20 

0 

25 

0.1930 

0 

HTr 

N/4 

N/8 

20 

0.0053 

25 

0.1930 

0.0274 

HTr 

20 

0.0099 

25 

0.1930 

0.0512 

HTr 

Neut. 

20 

0.0360 

25 

0.1930 

0.1240 

HTr 

N/2 

20 

0 

25 

0.1585 

0 

HTr 

N/4 

20 

0.0036 

25 

0.1585 

0.0217 

HTr 

N/8 

20 

0.0039 

25 

0.1585 

0.0245 

HTr 

Neut. 

20 

0.0018 

25 

0.1585 

0.0108 

HTr 

N/2 

20 

0 

25 

0.1600 

0 

HTr 

N/4 

20 

0 

25 

0.1600 

0 

HTr 

N/8 

20 

0.0018 

25 

0.1600 

0.0116 

HTr 

Neut. 

20 

0.0046 

25 

0.1600 

0.0286 

HTr 

.  N/2 

20 

0 

25 

0.1585 

0 

HTr 

N/4 

20 

0 

25 

0.1585 

0 

HTr 

N/8 

20 

0 

25 

0.1585 

0 

HTr 

Neut. 

20 

0 

25 

0.1585 

0 

HTr 

N/2 

20 

0.0049 

25 

0.1775 

0.0276 

HTr 

N/4 

20 

0.0116 

25 

0.1775 

0.0645 

HTr 

N/8 

20 

0.0112 

25 

0.1775 

0.0630 

HTr 

Neut. 

20 

0.0294 

25 

0.1775 

0.1655 

TABLE  XIII. 


Acid. 

Strength. 

Chloroform. 

Volume.  Alkaloid. 

Acid 

volume. 

Original 

total 

alkaloid. 

Factor. 

HTr 

N/2 

20 

0 

25 

0.1640 

0 

HTr 

N/4 

20 

0 

25 

0.1640 

0 

HTr 

N/8 

20 

0 

25 

0.1640 

0 

HTr 

Neut. 

20 

0 

25 

0.1640 

0 

HTr 

N/2 

20 

0 

25 

0.1680 

0 

HTr 

N/4 

20 

0 

25 

0.1680 

0 

HTr 

N/8 

20 

0.0040 

25 

0.1680 

0.0238 

HTr 

Neut. 

20 

0.0032 

25 

0.1680 

0.0191 

HTr 

N/2 

20 

0 

25 

0.1585 

0 

HTr 

N/4 

20 

0 

25 

0.1585 

0 

HTr 

N/8 

20 

0 

25 

0.1585 

0 

HTr 

Neut. 

20 

0 

25 

0.1585 

0 

HTr' 

N/2 

20 

0.0018 

25 

0.1595 

0.0114 

HTr 

N/4 

20 

0.0018 

25 

0.1595 

0.0114 

HTr 

N/8 

20 

0 

25 

0.1595 

0 

HTr 

Neut. 

20 

0.0024 

25 

0.1595 

0.0153 

HTr 

N/4 

20 

0 

25 

0.1595 

0 

HTr 

N/8 

20 

0 

25 

0.1595 

0 

HTr 

N/8 

20 

0.0014 

25 

0.1595 

0.0087 

HTr 

Neut. 

20 

0.0023 

25 

0.1595 

0.0144 

Cinchonine 


18 


JOURNAL  OF  THE 


TABLE  XIII. — Continued. 


Alkaloid 

Acid. 

Strength. 

Chloroform. 

Volume.  Alkaloid. 

Acid 

volume. 

Original 

total 

alkaloid. 

Factor. 

Quinine . 

.  .  .  HTr 

N/2 

20 

0 

25 

0.1625 

0 

HTr 

N/4 

20 

0 

25 

0.1625 

0 

HTr 

N/8 

20 

0.0014 

25 

0.1625 

0.0086 

Codeine . 

.  .  .  HTr 

N/2 

20 

0 

25 

0.1600 

0 

HTr 

N/4 

20 

0 

25 

0.1600 

0 

HTr 

N/8 

20 

0 

25 

0.1600 

0 

HTr 

Neut. 

20 

0 

25 

0.1600 

0 

Aconitine . 

.  .  .  HTr 

N/2 

20 

0 

25 

0.1930 

0 

HTr 

N/4 

20 

0 

25 

0.1930 

0 

HTr 

N/8 

20 

0.0052 

25 

0.1930 

0.0269 

HTr 

Neut. 

20 

0.0060 

25 

0.1930 

0.0310 

Atropine . 

. .  .  HTr 

N/2 

20 

0 

25 

0.1585 

0 

HTr 

N/4 

20 

0.0011 

25 

0.1585 

0.0069 

HTr 

N/8 

20 

0.0014 

25 

0.1585 

0.0088 

HTr 

Neut. 

20 

0.0021 

25 

0.1585 

0.0132 

Veratrine . 

. .  .  HTr 

N/2 

20 

0 

25 

0.1775 

0 

HTr 

N/4 

20 

0 

25 

0.1775 

0 

HTr 

N/8 

20 

0 

25 

0.1775 

0 

HTr 

Neut. 

20 

0.0024 

25 

0.1775 

0.0135 

TABLE  XIV. 


Alkaloid. 

Strength. 

Chloro¬ 

form 

volume. 

Alkaloid. 

Acid 

volume. 

Total 

alkaloid. 

Extrac¬ 

tion 

factor. 

References. 

Strychnine . 

.  .  N/2 

20 

0 

25 

0.1745 

0 

Authors 

N/4 

20 

0 

25 

0.1745 

0 

Authors 

N/8 

20 

0 

25 

0.1745 

0 

Authors 

N/50 

20 

0 

25 

0.1745 

0 

Authors 

Neut. 

20 

0.0127 

25 

0.1745 

0.0727 

Authors 

.17N 

50 

Traces 

70 

0.2000 

0 

Kippenberger 

1  percent. 

50? 

Traces 

50 

0.2610 

0 

Simmer 

Neut. 

50? 

Traces 

50 

0.2610 

0 

Simmer 

Brucine . 

.  .  N/2 

20 

0 

25 

0.1780 

0 

Authors 

N/4 

20 

0 

25 

0.1780 

0 

Authors 

N/8 

20 

0 

25 

0.1780 

0 

Authors 

Neut. 

20 

0.0143 

25 

0.1780 

0.0803 

Authors 

.17N 

50 

0.0020 

70 

0.2000 

0.0100 

Kippenberger 

Cinchonidine. . . . 

,  .  .  N/2 

20 

0 

25 

0.1715 

0 

Authors 

N/4 

20 

0 

25 

0.1715 

0 

Authors 

N/8 

20 

0 

25 

0.1715 

0 

Authors 

Neut. 

20 

0.0086 

25 

0.1715 

0.0503 

Authors 

Quinine . 

. . .  N/2 

20 

0 

25 

0.1740 

0 

Authors 

N/4 

20 

0 

25 

0.1740 

0 

Authors 

N/8 

20 

0 

25 

0.1740 

0 

Authors 

Neut. 

20 

0 

25 

0.1740 

0 

Authors 

.034N 

50 

0 

70 

0.2000 

0 

Kippenberger 

Atropine . 

.  .  .  .034N 

50 

0 

70 

0.2000 

0 

Kippenberger 

Neut. 

50 

0.0010 

70 

0.2000 

0.0050 

Kippenberger 

Morphine . 

.  .  .  .034N 

50 

0 

70 

0.2000 

0 

Kippenberger 

Aconitine . 

. . .  .255N 

50 

Traces 

70 

0.2000 

0 

Kippenberger 

.085N 

50 

0.0064 

70 

0.2000 

0.0320 

Kippenberger 

.017N 

50 

0.0130 

70 

0.2000 

0.0650 

Kippenberger 

Veratrine . 

.  .  .  .017N 

50 

Traces 

70 

0.2000 

0 

Kippenberger 

N/40 

50? 

Traces 

50 

0.2150 

0 

Simmer 

Neut. 

50? 

0.0374 

50 

0.2150 

0.1780 

Simmer 

Codeine . 

. .  .  .034N 

50 

0 

70 

0.2000 

0 

Kippenberger 

N/49 

50? 

Traces 

50 

0.2470 

0 

Simmer 

Neut. 

50? 

0.0276 

50 

0.2470 

0.1116 

Simmer 

Cocaine . . 

.  . .  .255N 

50 

0 

70 

0.2000 

0 

Kippenberger 

.017N 

50 

Traces 

70 

0.2000 

0 

Kippenberger 

Neut. 

50? 

0.0143 

50 

0.2640 

0.0540 

Simmer 

AMERICAN  PHARMACEUTICAL  ASSOCIATION 


1» 


TABLE  XV. 

Acid — Hydrochloric  Acid: 

Extrac¬ 

tion 

factor. 

Alkaloid. 

Strength. 

Chloro¬ 

form 

volume. 

Alkaloid. 

Acid 

volume. 

Total 

alkaloid. 

References. 

Strychnine . 

..  N/2 

20 

0.0522 

25 

0.080 

0.2895 

Authors 

N/4 

20 

0.0424 

25 

0.080 

0.2360 

Authors 

N/8 

20 

0.0394 

25 

0.080 

0.2182 

Authors 

Neut. 

20 

0.0085 

25 

0.080 

0.0472 

Authors 

6.75N 

50 

0.0920 

70 

0.200 

0.4600 

Kippenberger 

6.85N 

50? 

0.0233 

50 

0.2377 

0.1020 

Simmer 

2.74N 

50? 

0.0559 

50 

0.2377 

0.2360 

Simmer 

.274N 

50? 

0.0250 

50 

0.2377 

0.1050 

Simmer 

.027N 

50? 

0.0083 

50 

0.2377 

0.0340 

Simmer 

Neut. 

50? 

0.0158 

50 

0.2377 

0.0665 

Simmer 

Brucine . 

. .  .075N 

50 

0.0898 

70 

0.2000 

0.4490 

Kippenberger 

Cocaine . 

..  N/2 

20 

0 

25 

0.1790 

0 

Authors 

N/4 

20 

0 

25 

0.1790 

0 

Authors 

N/8 

20 

0.0432 

25 

0.1790 

0.2420 

Authors 

Neut. 

20 

0.0432 

25 

0.1790 

0.2420 

Authors 

2.74N 

50? 

0.0075 

50 

0.2240 

0.0335 

Simmer 

'  .274N 

50? 

0.0045 

50 

0.2240 

0.0210 

Simmer 

.027N 

50? 

0.0037 

50 

0.2240 

0.0165 

Simmer 

Neut. 

50? 

0.0490 

50 

0.2240 

0.4900 

Simmer 

.017N 

150 

0.0021 

70 

0.2000 

0.0110 

Kippenberger 

Atropine . 

. .  .075N 

50 

0.0014 

70 

0.2000 

0.0070 

Kippenberger 

2.74N 

50? 

0.0028 

50 

0.2250 

0.0124 

Simmer 

.027N 

50? 

0j 

50 

0.2250 

0i 

Simmer 

Neut. 

50? 

0i 

50 

0.2250 

0 

Simmer 

Morphine . 

. .  .075N 

50 

0 

70 

0.2000 

0 

Kippenberger 

1.37N 

50? 

0 

50 

0.2470 

0 

Simmer 

.027N 

50? 

0 

50 

0.2470 

0 

Simmer 

Neut. 

50? 

0.0045 

50 

0.2470 

0.0182 

Simmer 

Aconitine . 

.  .  .030N 

50 

0.0971 

70 

0.2000 

0.4850 

Kippenberger 

Veratrine . 

. .  .075N 

50 

0.0807 

70 

0.2000 

0.4035 

Kippenberger 

2.74N 

50? 

0.1248 

50 

0.2110 

0.5920 

Simmer 

.027N 

50? 

0.0327 

50 

0.2110 

0.1550 

Simmer 

Neut. 

50? 

0.0530 

50 

0.2110 

0.2520 

Simmer 

Codeine . 

.  .  .030N 

50 

Traces 

70 

0.2000 

0 

Kippenberger 

2.74N 

50? 

0.0079 

50 

0.2340 

0.0338 

Simmer 

.027N 

50? 

0.0015 

50 

0.2340 

0.0064 

Simmer 

Neut. 

50? 

0.0371 

50 

0.2340 

0.0158 

Simmer 

TABLE  XVI. 

Acid — Sulphuric  Acid: 


Alkaloid. 
Strychnine . 

Brucine . 

Morphine . 

Cinchonidine . 

Quinine . 

Codeine . 


Acid, 

Ether. 

Acid 

Original 

total 

alkaloid. 

Extraction 

strength. 

Volume. 

Alkaloid. 

volume. 

factor. 

N/2 

20 

0 

25 

0.1745 

0 

N/4 

20 

0 

25 

0.1745 

0 

N/8 

20 

0 

25 

0.1745 

0 

Neut. 

20 

0.0027 

25 

0.1745 

0.0055 

N/2 

20 

0 

25 

0.1780 

0 

N/4 

20 

0 

25 

0.1780 

0 

N/8 

20 

0 

25 

0.1780 

0 

Neut. 

20 

0 

25 

0.1780 

0 

N/2 

20 

0 

25 

0.1730 

0 

N/2 

20 

0 

25 

0.1730 

0 

N/8 

20 

0.0011 

25 

0.1730 

0.0063 

Neut. 

20 

0.0019 

25 

0.1730 

0.0010 

N/2 

20 

0 

25 

0.1715 

0 

N/4 

20 

0 

25 

0.1715 

0 

N/8 

20 

0 

25 

0.1715 

0 

Neut. 

20 

0.0040 

25 

0.1715 

0.0237 

N/2 

20 

0 

25 

0.1740 

0 

N/4 

20 

0 

25 

0.1740 

0 

N/8 

20 

0 

25 

0.1740 

0 

Neut. 

20 

0 

25 

0.1740 

0 

N/2 

20 

0 

25 

0.1720 

0 

N/4 

20 

0 

25 

0.1720 

0 

N/8 

20 

0.0024 

25 

0.1720 

0.0139 

Neut. 

20 

0 

25 

0.1720 

0 

20 


JOURNAL  OF  THE 


TABLE  XVII. 


Alkaloid. 


Aconitine . 


Atropine . 
Brucine.  . 


Cinchonidine . 


Cinchonine . 


Cocaine. 


Codeine. 


Acid* 

Chloroform.- 

Original 

Acid 

Weight 

Extraction 

Strength. 

Volume. 

alkaloid. 

volume. 

in  acid 
alkaloid. 

factor. 

HTr 

N/2 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/4 

20 

0.200 

50 

0.200 

1.00 

HTr 

N/8 

20 

0.200 

50 

0.200 

1.00 

HC1 

N/2 

20 

0.200 

25 

0.165 

0.830 

HCI 

N/4 

20 

0.200 

25  ' 

0.174 

0.872 

HC1 

N/8 

20 

0.200 

25 

0.186 

0.930 

HTr 

N/4 

20 

0.150 

25 

0.149 

0.994 

HTr 

N/8 

20 

0.200 

25 

0.199 

0.996 

HTr 

N/2 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/4 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/8 

20 

0.200 

25 

0.192 

0.964 

HTr 

N/8 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/2 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/4 

20 

0.200 

25 

0.199 

0.996 

Sulph. 

N/8 

20 

0.200 

25 

0.198 

0.994 

HCI 

N/2 

20 

0.200 

25 

0.1232 

0.617 

HCI 

N/4 

20 

0.200 

25 

0.1417 

0.7088 

HCI 

N/8 

20 

0.200 

25 

0.1555 

0.777 

HTr 

N/2 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/4 

20 

0.200 

50 

0.200 

1.00 

HTr 

N/8 

20 

0.200 

50 

0.200 

1.00 

Sulph. 

N/2 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/4 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/8 

20 

0.200 

25 

0.1988 

0.996 

HCI 

N/2 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/4 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/8 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/2 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/4 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/8 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/2 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/4 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/8 

20 

0.200 

25 

0.1998 

0.998 

HCI 

N/2 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/4 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/8 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/2 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/4 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/8 

20 

0.200 

25 

0.198 

0.990 

Sulph. 

N/2 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/4 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/8 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/2 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/4 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/8 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/2 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/4 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/8 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/2 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/4 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/8 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/2 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/4 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/8 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/2 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/4 

20 

0.200 

25 

0.200 

1.00 

HTr 

N/8 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/2 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/4 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/8 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/2 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/4 

20 

0.200 

25 

0.200 

1.00 

HCI 

N/8 

20 

0.200 

25 

0.200 

1.00 

Quinine, 


AMERICAN  PHARMACEUTICAL  ASSOCIATION 


21 


TABLE  XVII. — Continued. 


Alkaloid. 

Acid. 

Chloroform. 

Strength.  Volume 

Original 

alkaloid. 

Acid 

volume. 

Weight 
in  acid 
alkaloid. 

Extraction 

factor. 

Strychnine . 

.  .  .  HTr 

4N 

20 

0.200 

50 

0.200 

1.00 

HTr 

2N 

20 

0.200 

100 

0.200 

1.00 

HTr 

N 

20 

0.200 

100 

0.198 

0.996 

HTr 

N/2 

20 

0.200 

100 

0.198 

0.996 

HTr 

N/4 

20 

0.200 

95 

0.198 

0.996 

HTr 

N/8 

20 

0.200 

75 

0.198 

0.996 

HTr 

N/12 

20 

0.200 

75 

0.197 

0.986 

HTr 

N/25 

20 

0.200 

25 

0.187 

0.938 

HC1 

N/2 

20 

0.200 

25 

0.179 

0.900 

HC1 

N/4 

20 

0.200 

25 

0.175 

0.875 

HC1 

N/8 

20 

0.200 

25 

0.179 

0.899 

Veratrine . 

. . .  HTr 

N/2 

20 

0.200 

25 

0.198 

0.990 

HTr 

N/4 

20 

0.200 

25 

0.196 

0.990 

HTr 

N/8 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/2 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/4 

20 

0.200 

25 

0.200 

1.00 

Sulph. 

N/8 

20 

0.200 

25 

0.200 

1.00 

HC1 

N/2 

20 

0.200 

25 

0.126 

0.630 

HC1 

N/4 

20 

0.200 

25 

0.148 

0.742 

HC1 

N/8 

20 

0.200 

25 

0.157 

0.787 

V.  DISCUSSION  OF  RESULTS. 


In  looking  over  the  tables,  the  following  results  will  be  observed : 

Aconitine. — In  the  washing  of  a  solution  of  aconitine  tartrate  with  chloroform, 
it  is  seen  that  the  more  concentrated  the  acid  is,  the  less  alkaloid  will  be  removed. 
Hydrolysis  takes  place  in  the  neutral  solution  with  the  removal  of  about  11  percent 
of  the  alkaloid  in  the  free  state.  Whatever  alkaloid  is  removed  from  the  acid 
solution  is  removed  in  the  form  of  salt  and  not  in  the  free  state.  Aconitine  is  also 
removed  from  solution  in  sulphuric  acid,  provided  the  acid  is  less  than  ™  concen¬ 
tration,  but  in  much  smaller  amounts  than  from  tartaric  acid.  From  hydrochloric 
acid  solution  the  amount  of  alkaloid  removed  is  in  direct  proportion  to  the  strength 
of  the  acid  and  the  alkaloid  is  almost  entirely  removed  as  the  salt,  showing  that 
chloroform  is  a  fairly  good  solvent  for  the  hydrochlorides  of  aconitine. 

Atropine. — The  same  phenomena  will  be  observed  in  the  cases  of  the  sulphates 
and  tartrates  of  atropine,  namely,  that  as  acidity  increases,  less  alkaloid  will  be 
removed  by  ether  or  chloroform.  With  the  hydrochlorides  it  is  reversed,  and  as 
the  strength  of  the  acid  increases,  the  amount  of  alkaloid  removed  increases,  and  it 
is  removed  as  the  salt. 

Brucine. — Brucine  is  not  removed  from  tartaric  acid  solutions  of  strength 
greater  than  by  either  chloroform  or  ether,  although  with  a  decrease  in  the 
concentration  of  the  acid  from  that  point  down,  there  is  increased  hydrolytic  action 
with  the  removal  of  the  alkaloid  in  the  uncombined  state.  Sulphuric  acid  retains 
the  alkaloid  from  removal  by  either  chloroform  or  ether  from  acid  solution,  and 
ether  does  not  even  extract  any  from  the  neutral  solution.  From  a  solution 

of  the  hydrochloride  in  hydrochloric  acid,  45  percent  of  the  alkaloid  is  removed  by 
chloroform  and  most  of  it  as  the  salt. 

Cinchonidine  and  Cinchonine. — Cinchonidine,  cinchonine,  and  quinine  differ 
from  the  other  alkaloids  in  that  their  hydrochlorides  are  insoluble  in  chloroform. 
Many  of  the  hydrochlorides  of  the  other  alkaloids  are  soluble  to  a  great  extent 
in  this  solvent.  The  neutral  tartrates  and  sulphates  are  hydrolyzed  and  the  alka¬ 
loids  removed  by  both  ether  and  chloroform.  Cinchonidine  differs  from  cinchonine 


22 


JOURNAL  OF  THE 


in  that  the  tartrates  are  hydrolyzed  in  acid  solution  and  some  of  the  alkaloid 
removed  as  free  cinchonidine. 

Quinine. — Quinine  sulphate  is  neither  hydrolyzed  in  neutral  and  acid  solution 
nor  is  the  salt  soluble  in  either  ether  or  chloroform.  The  neutral  tartrate  is  only 
slightly  soluble  in  water  but  the  acid  solution  is  hydrolyzed  to  a  slight  extent, 
giving  up  quinine  in  both  the  free  and  combined  condition  to  chloroform  and  in 
the  free  state  to  ether. 

Morphine. — Neither  chloroform  nor  ether  remove  morphine  from  the  neutral 
or  acid  solution  of  the  tartrate.  The  neutral  sulphate  is  slightly  hydrolyzed  and 
some  free  morphine  found  in  the  ether. 

Strychnine. — Hydrolytic  action  takes  place  in  the-^-  tartaric  acid  and  neutral 
solution  of  the  strychnine  tartrate  and  some  alkaloid  is  removed  by  the  chloroform 
in  the  free  state.  Increase  in  acidity  with  both  the  sulphates  and  tartrates  causes 
a  decrease  in  the  amount  of  alkaloid  removed,  the  reverse  being  true  in  the 
case  of  the  hydrochlorides. 

Veratrine. — Veratrine  is  removed  in  appreciable  amounts  from  the  tartaric 
acid  solution  by  chloroform,  but  only  from  the  neutral  solution  by  ether.  Chloro¬ 
form  does  not  take  up  any  of  the  alkaloid  from  the  sulphuric  acid,  but  appreciably 
lowers  the  concentration  of  the  alkaloid  in  the  hydrochloric  acid  solutions. 

Codeine. — Neither  ether  nor  chloroform  will  remove  codeine  from  solution  in 
~2~or—^  tartaric  acid,  but  chloroform  removes  increasing  amounts  as  the  concen¬ 
tration  of  the  acid  decreases  from  that  point  on.  The  hydrochlorides  are  more 
soluble  in  chloroform  the  greater  the  concentration  of  the  acid.  Hydrolysis  takes 
place  in  the  neutral  solutions  and  much  codeine  is  removed. 

In  general,  the  following  principles  may  be  apparent  in  the  foregoing: 

1.  The  neutral  sulphates  and  tartrates  in  aqueous  solution  are  hydrolyzed 
to  a  certain  extent  with  the  subsequent  formation  of  free  alkaloid  and  acid.  This 
alkaloid  may  be  removed  by  the  immiscible  solvent. 

2.  With  an  increase  in  the  acidity  of  the  solution  the  hydrolytic  action  becomes 
less  and  the  amount  of  alkaloid  taken  up  in  the  free  state  decreases  with  the 
increase  in  acidity. 

3.  Many  of  the  acid  sulphates  and  tartrates  are  removed  as  salts  to  a  slight 
degree  by  chloroform  and  ether. 

4.  The  alkaloidal  hydrochlorides  tend  to  be  quite  soluble  in  chloroform,  and 
in  such  cases  the  solubility  increases  with  the  acidity  of  the  solution,  in  all  the 
cases  studied. 

By  means  of  this  data,  the  following  questions  may  be  answered : 

1.  What  conditions  of  acidity  would  completely  remove  the  alkaloid  from  its 
chloroform  solution? 

2.  Which  solvent,  chloroform  or  ether,  can  best  be  used  for  shaking  out  the 
neutral  or  acid  solution  of  the  alkaloidal  tartrates  or  sulphates,  without  removing 
the  alkaloid  ? 

3.  And  which  salts  are  least  easily  removed  by  chloroform  or  ether,  and  in  what 
concentration  of  acid,  either  by  hydrolysis  or  through  the  solubility  of  the  salt 
itself  in  the  immiscible  solvent? 

1.  The  best  conditions  of  acidity  for  completely  removing  the  alkaloids  from 
the  chloroform  solution.  Table  XVIII  gives  the  values  for  the  extraction 
of  0.2  Gm.  of  the  alkaloid  from  20  Cc.  of  the  solvent  chloroform,  by  the 
different  acids : 


AMERICAN  PHARMACEUTICAL  ASSOCIATION 


23 


TABLE  XVIII. 


Alkaloid.  Acid. 

Aconitine .  HTr 

Atropine .  HTr 

Brucine .  HTr 

Cinchonidine .  HC1 

and 

Cinchonine .  Sulph. 

Cocaine .  Sulph. 

and 

Codeine .  HC1 

Quinine .  HC1 

HTr 

Sulph. 

Strychnine .  HTr 

Veratrine .  HTr 

Sulph. 


Strength. 

Volume. 

N/8 

2  portions  of  25  Cc.  each 

N/8 

1  portion  of  25  and  1  of  10 

N/8 

1  portion  of  25  and  1  of  10 

N/8 

25  Cc. 

N/8 

1  portion  of  25  and  1  of  10 

N/8 

25  Cc. 

N/8 

25  Cc. 

N/8 

25  Cc. 

N/8 

25  Cc. 

N/8 

25  Cc. 

N/8 

3  portions  of  25  Cc.  each 

N/8 

25  Cc. 

N/8 

25  Cc. 

2.  The  best  solvent  for  shaking  out  the  neutral  and  acid  solutions  of  the  alka- 
loidal  tartrates,  without  the  loss  of  alkaloid : 


TABLE  XIX. 

Percent 

Alkaloid. 

Solvent. 

Strength  HTr. 

alkaloid 

removed. 

Aconitine . 

Ether 

N/4 

0 

Atropine . 

Chloroforir 

i  Slightly  acid 

1.0 

Brucine . 

Chloroform  N/8 

1.5 

Cinchonidine . 

Ether 

Slightly  acid 

1.2 

Cinchonine . 

Chloroforir 

i  N/8 

0 

Codeine . 

Ether 

N/8 

0 

Quinine . 

Ether 

N/8 

0.8 

Morphine . 

Either  one 

Slightly  acid 

0 

Strychnine . 

Ether 

Slightly  acid 

0 

Veratrine . 

Ether 

Slightly  N /8 

0 

3.  The  salts  that  are 

least  easily  removed  by  chloroform  or  ether  and 

the  best 

concentration  of  acid : 

TABLE  XX. 

Chloroform. 

Ether. 

Alkaloid. 

Salts. 

Strength 

Percent 

Salts.  Strength 

Percent 

acid. 

removed. 

acid. 

removed. 

Aconitine . 

N/4 

0 

Tartrate  N/4 

0 

Tartrate 

N/4 

0 

Atropine . 

.  .  .  HC1 

0.02N 

0 

Sulphate  N/10 

0 

Brucine . 

N/8 

0 

Sulphate  N/10 

0 

Cinchonine . 

N/8 

0 

Tartrate  N/8 

0.8 

Cinchonidine . 

. .  .  Sulphate 

N/8 

0 

Tartrate  N/8 

0 

Codeine . 

N/50 

0 

Sulphate  N/10 

0 

Quinine . 

N/50 

0 

Sulphate  N/10 

0 

Morphine . 

N/50 

0 

Tartrate  N/8 

0 

Strychnine . 

N/50 

0 

Tartrate  N/8 

0 

Veratrine . 

N/50 

0 

Tartrate  N/8 

0 

In  addition,  calculations  may  be  made  which  will  tell  how  many  shakings  from 
chloroform  solution  need  be  made  by  an  acid  to  completely  remove  the  alkaloid 
from  the  chloroform  solution.  If  94  percent  of  the  alkaloid  is  removed  in  the  first 
shaking  with  25.  Cc.  of  acid,  the  second  extraction  will  remove  94  percent  of  the 
6  percent  left,  or  5.86  percent.  Thus  these  two  extractions  will  remove  99.86  per¬ 
cent  of  the  alkaloid.  A  third  extraction  will  take  away  94  percent  of  the  remaining 
0.14  percent,  or  0.131  percent,  so  the  three  extractions  with  the  acid  will  make 
practically  a  complete  removal. 


24 


JOURNAL  OF  THE 


Table  XXI  shows  the  number  of  shakings  necessary  to  remove  0.2  Gm 
of  alkaloid  from  20  Cc.  of  a  chloroform  solution. 


TABLE  XXI. 


Percent 

Number  of 

Alkaloid. 

Acid. 

Strength. 

alkaloid 
removed  in 

shakings  for 
complete 

Total  acid 
volume. 

first  shaking. 

removal. 

Aconitine . 

HTr 

N/2 

100 

1 

25 

HTr 

N/4 

100 

1 

25 

HTr 

N/8 

100 

1 

25 

HC1 

N/2 

83.0 

4 

100 

HC1 

N/4 

87.2 

3 

75 

HC1 

N/8 

93.0 

3 

75 

Atropine . 

HTr 

N/4 

99.4 

2 

35 

HTr 

N/8 

99.6 

2 

25 

Brucine . 

HTr 

N/2 

100 

1 

25 

HTr 

N/4 

100 

1 

25 

HTr 

N/8 

96.4 

2 

35 

Sulph 

N/2 

100 

1 

25 

Sulph. 

•  N/4 

99.6 

2 

35 

Sulph. 

N/8 

99.4 

2 

35 

HC1 

N/2 

61.7 

6 

150 

HC1 

N/4 

70.8 

5 

125 

HC1 

N/8 

77.7 

4 

100 

Cinchonidine . 

HTr 

N/2 

100 

1 

25 

HTr 

N/4 

100 

1 

25 

HTr 

N/8 

100 

1 

25 

HC1 

N/2 

100 

1 

25 

HC1 

N/4 

100 

1 

25 

HC1 

N/8 

100 

1 

25 

Sulph. 

N/2 

100 

1 

25 

Sulph. 

N/4 

100 

1 

25 

Sulph. 

N/8 

99.5 

1 

35 

Cinchonine . 

HTr 

N/2 

100 

1 

25 

HTr 

N/4 

100 

1 

25 

HTr 

N/8 

100 

1 

25 

HC1 

N/2 

100 

1 

25 

HC1 

N/4 

100 

1 

25 

HC1 

N/8 

100 

1 

25 

Sulph. 

N/2 

100 

1 

25 

Sulph. 

N/4 

100 

1 

25 

Sulph. 

N/8 

99.8 

2 

35 

Cocaine . 

HTr 

N/2 

100 

1 

25 

HTr 

N/4 

100 

1 

25 

HTr 

N/8 

99.0 

2 

35 

Sulph. 

N/2 

100 

1 

25 

Sulph. 

N/4 

100 

1 

25 

Sulph. 

N/8 

100 

1 

25 

HC1 

N/2 

100 

1 

25 

HC1 

N/4 

100 

1 

25 

HC1 

N/8 

100 

r 

25 

Codeine . 

HTr 

N/2 

100 

i 

25 

HTr 

N/4 

100 

i 

25 

HTr 

N/8 

100 

i 

25 

Sulph. 

N/2 

100 

i 

25 

Sulph. 

N/4 

100 

i 

25 

Sulph. 

N/8 

100 

i 

25 

HC1 

N/2 

100 

i 

25 

HC1 

•  N/4 

100 

i 

25 

HC1 

N/8 

100 

i 

25 

Quinine . 

HTr 

N/2 

100 

i 

25 

HTr 

N/4 

100 

i 

25 

HTr 

N/8 

100 

i 

25 

Sulph. 

N/2 

100 

i 

25 

Sulph. 

N/4 

100 

i 

25 

Sulph. 

N/8 

100 

i 

25 

HC1 

N/2 

100 

i 

25 

HC1 

N/4 

100 

i 

25 

HC1 

N/8 

100 

i 

25 

AMERICAN  PHARMACEUTICAL  ASSOCIATION 


25 


TABLE  XXL — Continued. 


Percent 

Number  of 

Alkaloid. 

Acid. 

Strength. 

alkaloid 
removed  in 

shakings  for  Total  acid 

complete  volume. 

first  shaking. 

removal. 

Strychnine . 

HTr 

N 

100 

After  2  shakings  of  25  Cc.  each 

HTr 

N/2 

100 

After  4  shakings  of  25  Cc.  each 

HTr 

N 

99.6 

After  4  shakings  of  25  Cc.  each 

HTr 

N/2 

99.6 

After  4  shakings  of  25  Cc.  each 

HTr 

N/4 

99.6 

After  4  shakings  (3 X  25  -|-10Cc.) 

HTr 

N/8 

99.6 

After  3  shakings  of  25  Cc.  each 

HTr 

N/12 

99.6 

After  3  shakings  of  25  Cc.  each 

HTr 

N/25 

93.8 

After  1  shaking  of  25  Cc. 

For  complete  removal  from  N/25  acid,  2  shakings. 


HC1 

N/2 

90.0 

3 

75 

HC1 

N/4 

87.5 

3* 

75 

HC1 

N/8 

89.9 

3 

75 

Veratrine .  HTr 

N/2 

99.0 

2 

35 

HTr 

N/4 

98.0 

2 

35 

HTr 

'  N/8 

100.0 

1 

25 

HC1 

N/2 

63.0 

6 

150 

HC1 

N/4 

74.2 

5 

125 

HC1 

N/8 

78.7 

4 

100 

Sulph. 

N/2 

100 

1 

25 

Sulph. 

N/4 

100 

1 

25 

Sulph. 

N/8 

100 

1 

25 

VI.  SUMMARY. 

1.  The  most  practical  method  for  the  determination  of  alkaloids  involves  the 
extraction  of  the  alkaloid  from  an  aqueous  solution  by  means  of  an  immiscible 
solvent,  such  as  chloroform  or  ether. 

2.  It  further  involves  the  purification  of  the  alkaloidal  solution  by  removal  of 
gums,  colors,  etc.,  by  similar  methods. 

3.  Unless  conditions  are  carefully  guarded,  loss  of  alkaloid  as  salt  or  in  the 
free  state  will  occur  during  the  extraction. 

4.  The  equilibrium  conditions  for  the  following  systems  have  been  established, 
in  the  case  of  the  alkaloids  aconitine,  atropine,  brucine,  cinchonidine,  cinchonine, 
cocaine,  codeine,  morphine,  quinine,  strychnine,  and  veratrine : 

(a)  The  alkaloidal  tartrates,  tartaric  acid,  water  and  chloroform. 

( b )  The  alkaloidal  tartrates,  tartaric  acid,  water  and  ether. 

( c )  Certain  alkaloidal  sulphates,  sulphuric  acid,  water,  and  chloroform. 

( d )  Certain  alkaloidal  sulphates,  sulphuric  acid,  water,  and  ether. 

( e )  Certain  alkaloidal  hydrochlorides,  hydrochloric  acid,  water,  and 
chloroform. 

(/)  The  extraction  factors  have  been  determined  for  all  these  systems,  as  well 
as  those  described  in  the  literature,  and  the  most  favorable  conditions  for  extrac¬ 
tion  calculated. 

The  author  wishes  to  express  his  thanks  to  Dr.  G.  D.  Beal  under  whose  direc¬ 
tion  this  work  was  conducted,  for  his  advice  and  criticism,  and  to  Dr.  J.  H.  Beal 
for  financial  assistance. 

Laboratory  of  Organic  Analysis  of  the  University  of  Illinois. 

BIBLIOGRAPHY. 

1  Dragendorff :  Die  gerichtlich-chemische  Ermittelung  von  Giften,  4  Aufl.,  p.  151. 

2  Stas-Otto :  Ausmittelung  der  Gifte.,  7  Aufl.,  pp.  144  and  280. 

8  Kippenberger,  C. :  Grundlagen  fiir  den  Nachweis  von  Giftstoffen  bei  gerichtlich-chemischen 
Untersuchungen,  p.  56. 

4  Kippenberger,  C. :  Zts.  f.  Anal.  Ch.,  1900,  39,  290-314. 

4  Proelss,  Hans :  Apoth.  Ztg.,  1900,  16,  289-493. 

8  Springer,  Ed. :  Apoth.  Ztg.,  1901,  17,  225-226. 

*  Simmer :  Arch.  d.  Phar.,  1906,  244,  672. 

8  Marden  and  Elliott :  J.  Ind.  Eng.  Ch.,  6,  928. 

*  Kippenberger,  C. :  Zts.  f.  Anal.  Ch.,  1900,  39,  201-230. 


BIOGRAPHY 


The  author  attended  the  public  schools  of  New  York  City. 
His  preparatory  training  was  received  at  the  De  Witt  Clinton 
High  School  of  New  York  City. 

He  was  granted  the  degree  of  B.S.  by  Wesleyan  University 
in  1912,  and  that  of  M.S.  in  1913. 

During  1913-1914,  he  was  Assistant  in  Chemistry  at  the 
University  of  Illinois. 

In  the  period  from  September,  1914,  to  June,  1916,  he  was 
the  holder  of  the  Pharmaceutical  Research  Fellowship  at  the 
University  of  Illinois. 

In  April,  1915,  he  presented  a  paper  in  conjunction  with 
Dr.  G.  D.  Beal  at  the  New  Orleans  meeting  of  the  American 
Chemical  Society  on  the  subject,  “Some  New  Alkaloidal  Salts,” 
and  another  one,  also  with  Dr.  Beal,  at  the  Urbana  meeting  of 
the  Society  in  April,  1916,  on  the  subject,  “Alkaloidal  Deter¬ 
mination  by  Means  of  Immiscible  Solvents.” 

The  author  is  a  member  of  Sigma  Xi  and  Phi  Lambda 
Upsilon. 


